Inhibitors of the MYST Family of Lysine Acetyl Transferases

ABSTRACT

Provided herein are compounds of Formula (I). Methods for the preparation of the compounds of Formula (I) and intermediates useful in the preparation of the compounds of Formula (I) are described herein. The compounds of Formula (I) may be useful as inhibitors of the MYST family of lysine acetyltransferases (KATs) for the treatment of and/or prophylaxis of hyperproliferative diseases, disorders or conditions such as cancer. In particular, the compounds of Formula (I) are useful for the inhibition of KAT6A and KAT6B which are enzymes frequently mutated, overexpressed, amplified and/or translocated in cancer altering their normal expression, activity and function. The use of the compounds of Formula (I) in the manufacture of pharmaceutical compositions or for treating cancers is further described, including for treating cancer in combination with other anti-cancer agents.

RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. § 120 of U.S.application Ser. No. 18/190,224, filed Mar. 27, 2023, which claimspriority to U.S. Provisional Patent Applications 63/324,619, filed Mar.28, 2022, 63/324,624, filed Mar. 28, 2022, and 63/476,826, filed Dec.22, 2022. The disclosures of each of the above-referenced applicationsis incorporated by referenced herein in their entirety.

SEQUENCE LISTING

This application contains a sequence listing, which is being submittedherewith as an XML filed named “ISTX102USCON_SL.xml”, created on Jul.13, 2023, size 5457 bytes, which is incorporated by reference herein inits entirety.

FIELD

Provided herein are compounds of Formula (I). Methods for thepreparation of the compounds of Formula (I) and intermediates useful inthe preparation of the compounds of Formula (I) are described herein.The compounds of Formula (I) may be useful as inhibitors of the MYSTfamily of lysine acetyltransferases (KATs) for the treatment of and/orprophylaxis of hyperproliferative diseases, disorders or conditions suchas cancer. In particular, the compounds of Formula (I) are useful forthe inhibition of KAT6A and KAT6B which are enzymes frequently mutated,overexpressed, amplified and/or translocated in cancer, altering theirnormal expression, activity and function. The use of the compounds ofFormula (I) in the manufacture of pharmaceutical compositions or fortreating cancers is further described, including for treating cancer incombination with other anti-cancer agents.

BACKGROUND

Epigenetic regulation is a complex dynamic process that is criticallyimportant to cellular physiology and controls of gene expression,cell-cycle progression, cellular proliferation rates and stem cellmaintenance and differentiation (Allis and Jenuwein, Nature ReviewsGenetics 2016, Vol 17, pp. 487-500). Lysine acetyl transferases (KATs)and histone deacetylases (HDACs) play key roles in epigeneticregulation. KATs are a multi-family of enzymes that acetylate bothhistone and non-histone proteins. Histones are key components ofchromatin-DNA complex and their acetylation state is critical to theirfunction (Vernarecci, et al., Epigentics 2009, Vol. 5, pp. 105-111).KATs catalyze the post translational modification of histones throughacetylation of the epsilon amino group of lysine on histone proteins.This acetylation confers an open conformation to the chromatin andtypically promotes gene transcription.

One key family of KAT enzymes are known as the MYST family. This familyconsists of five members including KAT6A (also known as, MOZ or MYST3),KAT6B (also known as MORF or MYST4), KAT5 (also known as, Tip60), KAT7(also known as, HBO1 or MYST2) and Kat8 (also known as, MOF or MYST1)(Wiesel-Motiuk and Assaraf, Drug Resistance Updates 2020, Vol 53,100729; Wapenaar and Dekker, Clinical Epigenetics 2016, 8:59, 1 (DOI10.1186/s13148-016-0225-2), “Wapenaar et al., 2016”). The MYST family ofKATs is particularly important in regulation of the cell cycle(Carrozza, et al., Trends in Genetics 2003, Vol 19, pp. 321-329).

Dysregulation of the expression of KAT6 proteins supports tumorprogression (Trisciuoglio et al., Emerging role of histoneacetyltransferase in stem cells and Cancer. Stem Cells Int. Volume 2018,Article ID 8908751 (https://doi.org/10.1155/2018/8908751). Dysregulationthrough gene amplification, overexpression or mutation of KAT6A has beendocumented in multiple cancer types including breast, lungadenocarcinoma, ovarian, colon and rectal adenocarcinoma, and uterinecervix (Huang, et al., Molecular and Cellular Biology 2016, Vol 63, pp.1900-1907; Zack, et al., Nature Genetics 2013, Vol 45, pp. 1134-1140).It is reported that the locus that contains the gene for KAT6A (8p11-p12amplicon) is the 12^(th) most commonly amplified region of the genomeacross all cancer types (Zack, et al., 2013). In acute myeloid leukemia(AML), recurrent oncogenic fusions of KAT6A have been documented thatcan drive transformation to a malignant state (Sheikh, et al., Blood2015, Vol 125, pp. 1910-1921). Translocation of KAT6A and fusion to apartner such as CBP, p300, TIF2 and NCOA3 are known to lead toaggressive forms of AML (Sheikh, et al., 2015).

A key aspect of the catalytic mechanism of the KAT family of enzymes isthe acetylation of lysine residues using the cofactor Ac-CoA as anacetyl donor. One possible catalytic mechanism is the stepwise transferof the acetyl group from acetyl co-enzyme A (Ac-CoA) to transiently forman acetyl-enzyme intermediate. This acetyl-enzyme intermediatesubsequently is the source of the acetyl group that is transferred tothe substrate, typically a lysine on a histone (Wapenaar et al., 2016).In the MYST family of KATs there is a conserved cysteine that isacylated transiently as part of the catalytic cycle, as indicated withthe arrow below.

Amino Acid Sequence Alignment Near the Ac-CoA Binding Site of the MYSTFamily of KATs

KAT5  ESTEDYNVACILTLPPYQRR KAT8  ESPDGNNVACILTLPPYQRRKAT7  NSFLNYNVSCILTMPQYMRQ KAT6A HCQQKYNVSCIMILPQYQRKKAT6B LCQQKYNVSCIMIMPQHQRQ                

In one embodiment, the present disclosure provides compounds that maycovalently bind to this conserved cysteine.

Enzyme inhibitors that covalently interact with conserved cysteines ator near the active site of an enzyme are an important therapeuticmodality. Therapeutics which covalently and specifically react to form acovalent adduct with an active site cysteine offer potential advantagesin potency, possible lower dose, and increased target engagementduration resulting in reduced dosing frequency.

In addition to the role that KATs play in epigenetic regulation, KATsalso acetylate non-histone proteins (Glozak, et al., 2005; Das andKundu, 2008). Through modification of the acetylation state ofnon-histone proteins, KATs are involved modulating protein function andstability, protein-protein and protein-DNA interactions, and regulationof enzyme activity (Glozak, et al., Gene 2005, Vol 363, pp. 15-23; Dasand Kundu, IUBMB Life 2005, Vol 57, pp. 137-148).

Provided herein are compounds of Formula (I) which may inhibit the MYSTfamily of lysine acetyl transferases. The compounds described in thepresent disclosure inhibit MYST family members, including KAT6A. In someembodiments, the inhibition is through covalent modification of acysteine residue at the Ac-CoA binding site. The compounds describedherein are useful for the treatment of cancer including breast cancer,lung cancer, ovarian cancer, colon cancer, prostate cancer,uterine/cervical cancer and leukemia. The compounds of Formula I can beused as single agents or in combination with a standard of caretreatment for a particular cancer.

SUMMARY

Provided herein are compounds, pharmaceutical compositions comprisingthe compounds, and methods of using the compounds and compositions intreating a condition, disease, or disorder by inhibiting MYST family oflysine acetyl transferases, including KAT6A and KAT6B, includinghyperproliferative disorders and cancer.

In one aspect, provided is a compound of Formula (I):

-   -   where R¹ is C₃-C₈-cycloalkyl optionally substituted with 1, 2,        or 3 R^(1a); C₃-C₈-cycloalkyl-C₁-C₆alkyl where the        C₃-C₈-cycloalkyl is optionally substituted with 1, 2, or 3 Ria;        phenyl optionally substituted with 1, 2, or 3 R^(1b);        phenyl-C₁-C₆alkyl optionally substituted with 1, 2, or 3 R^(1b);        naphthyl optionally substituted with 1, 2, or 3 R^(1b); or 5- or        6-membered monocyclic heteroaryl optionally substituted with 1,        2, or 3 R^(1b); 8- to 10-membered bicyclic heteroaryl optionally        substituted with 1, 2, or 3 R^(1b);    -   each R^(1a) is independently selected from hydrogen, halo,        C₁-C₆alkoxy, and C₃-C₈-cycloalkyloxy;    -   each R^(1b) is independently selected from hydrogen, halo,        C₁-C₆alkyl, C₁-C₆alkoxy, hydroxyalkyloxy,        —O-alkylene-NR^(1b1)R^(1b4),        —O-alkylene-C(O)OR^(1b1)-O-alkylene-O-alkylene-NR^(1b1)R^(1b4),

cyano, —(CH₂)₀₋₂C(O)—OR^(1b1), —(CH₂)₀₋₂C(O)NR^(1b1)R^(1b2),—(CH₂)₀₋₂NR^(1b1)C(O)R^(1b3), —(CH₂)₀₋₂OH, and C₃-C₈-cycloalkyloxy;

-   -   R^(1b1) is hydrogen or C₁-C₆alkyl; R^(1b2) is hydrogen or        C₁-C₆alkyl; R^(1b3) is hydrogen or C₁-C₆alkyl; and R^(1b4) is        hydrogen,

-   -   R² is selected from the group consisting of:

-   -   R^(2a) is hydrogen or C₁-C₆alkyl;    -   each R^(2b) is independently hydrogen, halo, —(CH₂)₀₋₂OH,        C₁-C₃alkyl, cyclopropyl, cyano, —CHF₂, —CF₃, C₁-C₄alkoxy,        —OCHF₂, —OCF₃, or C₃-C₈cycloalkyloxy;    -   each R^(2e) is independently hydrogen, —OH, halo, C₁-C₆alkyl,        halo-C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆alkoxy, halo-C₁-C₆alkoxy,        or C₃-C₈cycloalkyloxy;

-   -   wherein, for rings (a), (b), and (c)        -   one X¹ is CR³ and the other X¹ are independently selected            from N and CR²b;        -   R^(2d) is hydrogen, halo, C₁-C₆alkyl, C₁-C₆cycloalkyl,            C₁-C₆alkoxy, or C₃-C₈-cycloalkyloxy; R³ is —(CH₂)₀₋₂Y or            —(CH₂)₀₋₂-L-Y;        -   L is —L¹—L²—L³—, where L¹, L² and L³ are each independently            a bond, —CRR—, O, S(O)₀₋₂, C(O) or NR, where each R is            independently H or alkyl;        -   Y is a 5-membered monocyclic heteroaryl substituted with            R^(Y) and optionally substituted with R^(2e); Y is a            6-membered monocyclic aryl or heteroaryl substituted with            R^(Y) and optionally substituted with 1 or 2 R^(2e); Y is an            8-membered bicyclic heteroaryl substituted with R^(Y) and            optionally substituted with 1 or 2 R^(2e); Y is a 9-membered            bicyclic heteroaryl substituted with R^(Y) and optionally            substituted with 1, 2, or 3 R^(2e); Y is a 10-membered            bicyclic heteroaryl substituted with R^(Y) and optionally            substituted with 1, 2, or 3 R^(2e); Y is a 8- or 9-membered            bicyclic heterocyclic substituted with R^(Y) and optionally            substituted with 1 or 2 R^(2e); Y is a 4-9-membered            monocyclic or bicyclic heterocycloalkyl substituted with            R^(Y) and optionally substituted with 1 or 2 R^(2e); Y is

-   -   -    Y is —(CH₂)₀₋₃NR^(3b)R^(Y); or Y is            —(CH₂)₀₋₃NR^(3b)C(O)R^(Y); R^(Y) is            —(CH₂)₀₋₃NR^(3b)C(O)R^(3a), —(CH₂)₀₋₂NR^(3b)S(O)₂R^(3a),            —C(O)R^(3a), —S(O)₂R^(3a), —C(O)NR^(3b)R^(3a),            C₃-C₈heterocycloalkyl substituted with —C(O)R^(3a);            —(CH₂)₀₋₃NR^(3b)(C₁-C₆alkylene)NR^(3b1)C(O)R^(3a),            —(CH₂)₀₋₃NR^(3b)(C₁-C₆alkylene)NR^(3b1)S(O)₂R^(3a),            —(CH₂)₀₋₃NR^(3b)C(O)(C₁-C₆alkylene)NR^(3b1)C(O)R^(3a), or            —(CH₂)₀₋₃NR^(3b)C(O)(C₁-C₆alkylene)NR^(3b1)S(O)₂R^(3a),        -   R^(3a), R^(3b) and R^(3b1) are selected from (i), (ii) or            (iii):        -   (i) one of R^(3a), R^(3b) and R^(3b1) is selected from group            a): C₁-C₆alkyl substituted with 1 or 2 halo which are            independently selected; C₁-C₆alkyl substituted with cyano;            C₁-C₆alkyl substituted with fluoroalkoxy; C₁-C₆alkyl            substituted with aryloxy or heteroaryloxy, each of which is            optionally substituted with 1-3 substituents each            independently selected from halo, C₁₋₆alkyl, C₂₋₆alkenyl,            C₁₋₆alkoxy, cyano, C₃₋₈cycloalkyl or C₃₋₈heterocycloalkyl;            C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano;            C₂-C₆alkenyl substituted with halo;            —CH═CH—CH₂—NR^(3c)R^(3d); —CH═CH—CH₂—O—C₁-C₆alkyl;            C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;            —CH≡CH—CH₂—NR^(3c)R^(3d); CH≡CH—CH₂—OH;            —CH≡CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted with            cyano; chloropyridyl; fluoropyridyl; chloropyrazinyl;            fluoropyrazinyl; chloropyrimidinyl; fluoropyrimidinyl;            pentafluorophenyl; tetraflurophenyl; trifluorophenyl,            difluorophenyl; and monofluorophenyl; and the others of            R^(3a), R^(3b) and R^(3b1) are selected from group b):            hydrogen, and C₁-C₆alkyl; or        -   (ii) one of R^(3a), R^(3b) and R^(3b1) is selected from            group a): hydrogen; C₁-C₆alkyl; C₁-C₆alkyl substituted with            aryloxy or heteroaryloxy, each of which is optionally            substituted with 1-3 substituents each independently            selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, cyano,            C₃₋₈cycloalkyl or C₃₋₈heterocycloalkyl; C₂-C₆alkenyl;            C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;            spirocycloalkyl; pyridyl; pyrimidinyl; and phenyl; and the            others of R^(3a), R^(3b) and R^(3b1) are selected from group            b): hydrogen, and C₁-C₆alkyl; or        -   (iii) R^(3a), R^(3b) and R^(3b1) are each independently            hydrogen or C₁-C₆alkyl; R^(3c) is hydrogen, or C₁-C₆alkyl,            and R^(3d) is hydrogen, or C₁-C₆alkyl; or R^(3c) and R^(3d)            together with the nitrogen to which they are attached form a            3-8 membered, saturated ring where the other 2-7 ring            members are carbon; and        -   HET1 is C₃-C₈heterocycloalkyl;

    -   wherein, for ring (d),        -   X^(2a) is O or S;        -   one X² is CR⁴ and the other X² are independently selected            from N and CR^(2b);        -   R⁴ is —(CH₂)₀₋₃NR^(4b)C(O)R^(4a),            —(CH₂)₀₋₂NR^(4b)S(O)₂R^(4a), —C(O)R^(4a),            —C(O)NR^(4b)R^(4a),            —NR^(4b)(C₁-C₆alkylene)NR^(4b1)C(O)R^(4a),            —(CH₂)₀₋₃NR^(4b)C(O)(C₁-C₆alkylene)NR^(4b1)C(O)R^(4a),            —C(O)NR^(4b)(C₁-C₆alkylene)NR^(4b1)C(O)R^(4a),            —C(O)—HET1-C(O)R^(4a), —C(O)—HET1—NR^(4b)C(O)R^(4a),            —(CH₂)₀₋₃NR^(4b)C(O)-HET1-C(O)R^(4a), C₃-C₈heterocycloalkyl            substituted with —C(O)R^(4a) (preferably where the            C₃-C₈heterocycloalkyl is attached to ring (d) through a            carbon in the C₃-C₈heterocycloalkyl ring); or            —(CH₂)₀₋₂HET2-C(O)R^(4a);        -   R^(4a), R^(4b) and R^(4b1) is selected from (i), (ii) and            (iii):        -   (i) one of R^(4a), R^(4b) and R^(4b1) is selected from group            a): alkyl substituted with 1 or 2 halo which are            independently selected; C₁-C₆alkyl substituted with cyano;            C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano;            C₂-C₆alkenyl substituted with halo;            —CH═CH—CH₂—NR^(4c)R^(4d); —CH═CH—CH₂—O—C₁-C₆alkyl;            C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;            —CH≡CH—CH₂—NR^(4c)R^(4d); CH≡CH—CH₂—OH;            CH—CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted with            cyano; chloropyridyl, fluoropyridyl, chloropyrazinyl,            fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl,            pentafluorophenyl; tetraflurophenyl; trifluorophenyl;            difluorophenyl; and monofluorophenyl; and the others of            R^(4a), R^(4b) and R^(4b1) are selected from group b):            hydrogen, and C₁-C₆alkyl;        -   (ii) one of R^(4a), R^(4b) and R^(4b1) is selected from            group a): hydrogen; alkyl; C₂-C₆alkenyl; C₃-C₈cycloalkenyl;            —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl; spirocycloalkyl;            pyridyl; pyrazinyl; pyrimidinyl; and phenyl; and the others            of R^(4a), R^(4b) and R^(4b1) are selected from group b):            hydrogen, and C₁-C₆alkyl; or        -   (iii) R^(4a), R^(4b) and R^(4b1) are each independently            hydrogen or C₁-C₆alkyl;        -   R^(4c) is hydrogen, or C₁-C₆alkyl, and R^(4d) is hydrogen,            or C₁-C₆alkyl; or R^(4c) and R^(4d) together with the            nitrogen to which they are attached form a 3-8 membered,            saturated ring where the other 2-7 ring members are carbon;        -   HET1 is C₃-C₈heterocycloalkyl; and        -   HET2 is a 8-, 9- or 10-membered bicyclic heterocyclic            optionally substituted with 1 or 2 R^(2e);

    -   wherein, for ring (e) and (f),        -   R⁵ is a 5-membered monocyclic heteroaryl substituted with Z            and optionally substituted with R^(2e); R⁵ is a 6-membered            monocyclic heteroaryl substituted with Z and optionally            substituted with R^(2e); R⁵ is —C(O)N(R^(5b))₂; R⁵ is            heterocycloalkyl substituted with Z and optionally            substituted with R^(2e); R⁵ is —(CH₂)₀₋₂O-HET1-Z;            -   R⁵ is —(CH₂)₀₋₂O—Z;        -   Z is —(CH₂)₀₋₃NR^(5b)C(O)R^(5a),            —(CH₂)₀₋₂NR^(5b)S(O)₂R^(5a), —C(O)R^(5a), —S(O)₂R^(5a),            —(CH₂)₀₋₃—C(O)NR^(5b)R^(5a),            —(CH₂)₀₋₃NR^(5b)(C₁-C₆alkylene)NR^(5b1)C(O)R^(5a),            C₃-C₈heterocycloalkyl substituted with —NR^(5b)C(O)R^(5a),            C₃-C₈heterocycloalkyl substituted with —S(O)₂R^(5a), or            C₃-C₈heterocycloalkyl substituted with —C(O)R^(5a);        -   R^(5a), R^(5b) and R^(5b1) are selected from (i), (ii) or            (iii):        -   (i) one of R^(5a), R^(5b) and R^(5b1) is selected from group            a): C₁-C₆alkyl substituted with 1 or 2 halo which are            independently selected; C₁-C₆alkyl substituted with cyano;            C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano;            C₂-C₆alkenyl substituted with halo;            —CH═CH—CH₂—NR^(5c)R^(5d); —CH═CH—CH₂—O—C₁-C₆alkyl;            C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;            —CH≡CH—CH₂—NR^(5c)R^(5d); CH≡CH—CH₂—OH;            CH—CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted with            cyano; chloropyridyl, fluoropyridyl, chloropyrazinyl,            fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl,            pentafluorophenyl; tetraflurophenyl; trifluorophenyl;            difluorophenyl; and monofluorophenyl and the other of            R^(5a), R^(5b) and R^(5b1) are selected from group b):            hydrogen, and C₁-C₆alkyl;        -   (ii) one of R^(5a), R^(5b) and R^(5b1) is selected from            group a): hydrogen; C₁-C₆alkyl; C₂-C₆alkenyl;            C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;            spirocycloalkyl; pyridyl; pyrazinyl; pyrimidinyl; and            phenyl; and the other of R⁵, R^(5b) and R^(5b1) are selected            from group b): hydrogen, and C₁-C₆alkyl; or        -   (iii) R^(5a), R^(5b) and R^(5b1) are each independently            hydrogen or C₁-C₆alkyl;        -   each R^(5c) is independently hydrogen, or C₁-C₆alkyl and            R^(5d) is hydrogen, or C₁-C₆alkyl; or R^(5c) and R^(5d)            together with the nitrogen to which they are attached form a            3-8 membered saturated ring where the other 2-7 ring members            are carbon;        -   HET1 is C₃-C₈heterocycloalkyl;

    -   wherein, for ring (g),        -   Q¹ is CR^(Q1), Q² is N, and Q³ is O; or Q¹ is CR^(Q1), Q² is            O, and Q³ is N; or Q¹ is S, Q² is N, and Q³ is N; or Q¹ is            N, Q² is N, and Q³ is 0; or Q¹ is O, Q² is N, and Q³ is N;            where R^(Q1) is hydrogen, C(O)C₁-C₆alkyl, or C₁;        -   R⁶ is a 5- or 6-membered monocyclic heteroaryl substituted            with Q and optionally substituted with R^(2e); or R⁶ is Q;        -   Q is —(CH₂)₀₋₃NR^(6b)C(O)R^(6a),            —(CH₂)₀₋₂NR^(6b)S(O)₂R^(6a), —C(O)R^(6a),            —C(O)NR^(6b)R^(6a), or C₃-C₈heterocycloalkyl substituted            with —C(O)R^(6a),        -   R^(6a) and R^(6b) are selected from (i), (ii) or (iii):        -   (i) one of R^(6a) and R^(6b) is selected from group a):            C₁-C₆alkyl substituted with 1 or 2 halo which are            independently selected; C₁-C₆alkyl substituted with cyano;            C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano;            C₂-C₆alkenyl substituted with halo;            —CH═CH—CH₂—NR^(6c)R^(6d); —CH═CH—CH₂—O—C₁-C₆alkyl;            C₃-C₈cycloalkenyl; —C(O)cycloalkyl; alkynyl;            —CH≡CH—CH₂—NR^(6c)R^(6d); CH≡CH—CH₂—OH;            CH≡CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted with            cyano; chloropyridyl, fluoropyridyl, chloropyrazinyl,            fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl,            pentafluorophenyl; tetraflurophenyl; trifluorophenyl;            difluorophenyl; and monofluorophenyl; and the other of            R^(6a) and R^(6b) is selected from group b): hydrogen, and            C₁-C₆alkyl;        -   (ii) one of R^(6a) and R^(6b) is selected from group a):            C₁-C₆alkyl; C₂-C₆alkenyl; C₃-C₈cycloalkenyl;            —C(O)cycloalkyl; alkynyl; spirocycloalkyl; pyridyl;            pyrazinyl; pyrimidinyl; and phenyl; and the other of R^(6a)            and R^(6b) is selected from group b): hydrogen, and            C₁-C₆alkyl; or        -   (iii) R^(6a) and R^(6b) are each independently hydrogen, and            C₁-C₆alkyl;        -   R^(6c) is hydrogen, or C₁-C₆alkyl and R^(6d) is hydrogen, or            C₁-C₆alkyl; or R^(6c) and R^(6d) together with the nitrogen            to which they are attached form a 3-8 membered saturated            ring where the other 2-7 ring members are carbon; and each            R⁷ is independently hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy, or            C₃-C₈cycloalkyl;

    -   or a pharmaceutically acceptable salt or salts thereof; and/or a        stereoisomer or mixture of stereoisomers thereof.

In one aspect, provided is a compound of Formula (I):

-   -   where R¹ is C₃-C₈-cycloalkyl optionally substituted with 1, 2,        or 3 R^(1a); C₃-C₈-cycloalkyl-C₁-C₆alkyl where the        C₃-C₈-cycloalkyl is optionally substituted with 1, 2, or 3        R^(1a); phenyl optionally substituted with 1, 2, or 3 R^(1b);        phenyl-C₁-C₆alkyl optionally substituted with 1, 2, or 3 R^(1b);        naphthyl optionally substituted with 1, 2, or 3 R^(1b); or 5- or        6-membered monocyclic heteroaryl optionally substituted with 1,        2, or 3 R^(1b); 8- to 10-membered bicyclic heteroaryl optionally        substituted with 1, 2, or 3 Rib;    -   each R^(1a) is independently selected from hydrogen, halo,        C₁-C₆alkoxy, and C₃-C₈-cycloalkyloxy;    -   each R^(1b) is independently selected from hydrogen, halo,        C₁-C₆alkyl, C₁-C₆alkoxy, hydroxyalkyloxy,        —O-alkylene-NR^(1b1)R^(1b4), —O-alkylene-C(O)OR^(1b1),        —O-alkylene-O—O-alkylene-C(O)—NR^(1b1)R^(1b4),

cyano, —(CH₂)₀₋₂C(O)—OR^(1b1), —(CH₂)₀₋₂C(O)NR^(1b1)R^(1b2),—(CH₂)₀₋₂NR^(1b1)C(O)R^(1b3), —(CH₂)₀₋₂OH, and C₃-C₈-cycloalkyloxy;R^(1b1) is hydrogen or C₁-C₆alkyl; R^(1b2) is hydrogen or C₁-C₆alkyl;R^(1b3) is hydrogen or C₁-C₆alkyl; and R^(1b4) is hydrogen,

-   -   R² is selected from the group consisting of

-   -   R^(2a) is hydrogen or C₁-C₆alkyl;    -   each R^(2b) is independently hydrogen, halo, —(CH₂)₀₋₂OH,        C₁-C₃alkyl, cyclopropyl, cyano, —CHF₂, —CF₃, C₁-C₄alkoxy,        —OCHF₂, —OCF₃, or C₃-C₈cycloalkyloxy;    -   each R^(2e) is independently hydrogen, —OH, halo, C₁-C₆alkyl,        halo-C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆alkoxy, halo-C₁-C₆alkoxy,        or C₃-C₈cycloalkyloxy;

-   -   wherein, for rings (a), (b), and (c)        -   one X¹ is CR³ and the other X¹ are independently selected            from N and CR²b.        -   R^(2d) is hydrogen, halo, C₁-C₆alkyl, C₁-C₆cycloalkyl,            C₁-C₆alkoxy, or C₃-C₈-cycloalkyloxy;        -   R³ is —(CH₂)₀₋₂Y;        -   Y is a 5-membered monocyclic heteroaryl substituted with            R^(Y) and optionally substituted with R^(2e); Y is a            6-membered monocyclic aryl or heteroaryl substituted with            R^(Y) and optionally substituted with 1 or 2 R^(2e); Y is an            8-membered bicyclic heteroaryl substituted with R^(Y) and            optionally substituted with 1 or 2 R^(2e); Y is a 9-membered            bicyclic heteroaryl substituted with R^(Y) and optionally            substituted with 1, 2, or 3 R^(2e); Y is a 10-membered            bicyclic heteroaryl substituted with R^(Y) and optionally            substituted with 1, 2, or 3 R^(2e); Y is a 8- or 9-membered            bicyclic heterocyclic substituted with R^(Y) and optionally            substituted with 1 or 2 R^(2e); Y is a 4-9-membered            monocyclic or bicyclic heterocycloalkyl substituted with            R^(Y) and optionally substituted with 1 or 2 R^(2e); Y is

-   -   -    Y is —(CH₂)₀₋₃NR^(3b)R^(Y); or Y is            —(CH₂)₀₋₃NR^(3b)C(O)R^(Y);        -   R^(Y) is —(CH₂)₀₋₃NR^(3b)C(O)R^(3a),            —(CH₂)₀₋₂NR^(3b)S(O)₂R^(3a), —C(O)R^(3a), —S(O)₂R^(3a),            —C(O)NR^(3b)R^(3a), C₃-C₈heterocycloalkyl substituted with            —C(O)R^(3a);            —(CH₂)₀₋₃NR^(3b)(C₁-C₆alkylene)NR^(3b1)C(O)R^(3a),            —(CH₂)₀₋₃NR^(3b)(C₁-C₆alkylene)NR^(3b1)S(O)₂R^(3a),            —(CH₂)₀₋₃NR^(3b)C(O)(C₁-C₆alkylene)NR^(3b1)C(O)R^(3a), or            —(CH₂)₀₋₃NR^(3b)C(O)(C₁-C₆alkylene)NR^(3b1)S(O)₂R^(3a), one            of R^(3a), R^(3b) and R^(3b1) is selected from group a):            C₁-C₆alkyl substituted with 1 or 2 halo which are            independently selected; C₁-C₆alkyl substituted with cyano;            C₁-C₆alkyl substituted with fluoroalkoxy; C₁-C₆alkyl            substituted with aryloxy or heteroaryloxy, each of which is            optionally substituted with 1-3 substituents each            independently selected from halo, C₁₋₆alkyl, C₂₋₆alkenyl,            C₁₋₆alkoxy, cyano, C₃₋₈cycloalkyl or C₃-heterocycloalkyl;            C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano;            C₂-C₆alkenyl substituted with halo;            —CH═CH—CH₂—NR^(3c)R^(3d); —CH═CH—CH₂—O—C₁-C₆alkyl;            C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;            —CH≡CH—CH₂—NR^(3c)R^(3d); CH≡CH—CH₂—OH;            —CH≡CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted with            cyano; chloropyridyl; fluoropyridyl; chloropyrazinyl;            fluoropyrazinyl; chloropyrimidinyl; fluoropyrimidinyl;            pentafluorophenyl; tetraflurophenyl; trifluorophenyl,            difluorophenyl; and monofluorophenyl; and the others of            R^(3a), R^(3b) and R^(3b1) are selected from group b):            hydrogen, and C₁-C₆alkyl;        -   R^(3c) is hydrogen, or C₁-C₆alkyl, and R^(3d) is hydrogen,            or C₁-C₆alkyl; or R^(3c) and R^(3d) together with the            nitrogen to which they are attached form a 3-8 membered,            saturated ring where the other 2-7 ring members are carbon;            and        -   HET1 is C₃-C₈heterocycloalkyl;

    -   wherein, for ring (d),        -   X^(2a) is O or S;        -   one X² is CR⁴ and the other X² are independently selected            from N and CR^(2b);        -   R⁴ is —(CH₂)₀₋₃NR^(4b)C(O)R^(4a),            —(CH₂)₀₋₂NR^(4b)S(O)₂R^(4a), —C(O)R^(4a),            —C(O)NR^(4b)R^(4a),            —NR^(4b)(C₁-C₆alkylene)NR^(4b1)C(O)R^(4a),            —(CH₂)₀₋₃NR^(4b)C(O)(C₁-C₆alkylene)NR^(4b1)C(O)R^(4a),            —C(O)NR^(4b)(C₁-C₆alkylene)NR^(4b1)C(O)R^(4a),            —C(O)—HET1-C(O)R^(4a), —C(O)—HET1—NR^(4b)C(O)R^(4a),            —(CH₂)₀₋₃NR^(4b)C(O)-HET1-C(O)R^(4a), C₃-C₈heterocycloalkyl            substituted with —C(O)R^(4a) (preferably where the            C₃-C₈heterocycloalkyl is attached to ring (d) through a            carbon in the C₃-C₈heterocycloalkyl ring); or            —(CH₂)₀₋₂HET2-C(O)R^(4a);        -   one of R^(4a), R^(4b) and R^(4b1) is selected from group a):            alkyl substituted with 1 or 2 halo which are independently            selected; C₁-C₆alkyl substituted with cyano; C₂-C₆alkenyl;            C₂-C₆alkenyl substituted with cyano; C₂-C₆alkenyl            substituted with halo; —CH═CH—CH₂—NR^(4c)R^(4d);            —CH═CH—CH₂—O—C₁-C₆alkyl; C₃-C₈cycloalkenyl;            —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;            —CH≡CH—CH₂—NR^(4c)R^(4d); CH≡CH—CH₂—OH;            CH≡CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted with            cyano; chloropyridyl, fluoropyridyl, chloropyrazinyl,            fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl,            pentafluorophenyl; tetraflurophenyl; trifluorophenyl;            difluorophenyl; and monofluorophenyl; and        -   the other of R^(4a), R^(4b) and R^(4b1) are selected from            group b): hydrogen, and C₁-C₆alkyl;        -   R^(4c) is hydrogen, or C₁-C₆alkyl, and R^(4d) is hydrogen,            or C₁-C₆alkyl; or R^(4c) and R^(4d) together with the            nitrogen to which they are attached form a 3-8 membered,            saturated ring where the other 2-7 ring members are carbon;        -   HET1 is C₃-C₈heterocycloalkyl; and        -   HET2 is a 8-, 9- or 10-membered bicyclic heterocyclic            optionally substituted with 1 or 2 R^(2e);

    -   wherein, for ring (e) and (f),        -   R⁵ is a 5-membered monocyclic heteroaryl substituted with Z            and optionally substituted with R^(2e); R⁵ is a 6-membered            monocyclic heteroaryl substituted with Z and optionally            substituted with R^(2e); R⁵ is —C(O)N(R^(5b))Z; R⁵ is            heterocycloalkyl substituted with Z and optionally            substituted with R^(2e); R⁵ is —(CH₂)₀₋₂O-HET1-Z; R⁵ is            —(CH₂)₀₋₂O—Z;        -   Z is —(CH₂)₀₋₃NR^(5b)C(O)R^(5a),            —(CH₂)₀₋₂NR^(5b)S(O)₂R^(5a), —C(O)R^(5a), —S(O)₂R^(5a),            —(CH₂)₀₋₃—C(O)NR^(5b)R^(5a),            —(CH₂)₀₋₃NR⁵b(C₁-C₆alkylene)NR^(5b1)C(O)R^(5a),            C₃-C₈heterocycloalkyl substituted with —NR^(5b)C(O)R^(5a),            C₃-C₈heterocycloalkyl substituted with —S(O)₂R^(5a), or            C₃-C₈heterocycloalkyl substituted with —C(O)R^(5a);        -   one of R^(5a), R^(5b) and R^(5b1) is selected from group a):            C₁-C₆alkyl substituted with 1 or 2 halo which are            independently selected; C₁-C₆alkyl substituted with cyano;            C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano;            C₂-C₆alkenyl substituted with halo;            —CH═CH—CH₂—NR^(5c)R^(5d); —CH═CH—CH₂—O—C₁-C₆alkyl;            C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;            —CH≡CH—CH₂—NR^(5c)R^(5d); CH≡CH—CH₂—OH;            CH≡CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted with            cyano; chloropyridyl, fluoropyridyl, chloropyrazinyl,            fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl,            pentafluorophenyl; tetraflurophenyl; trifluorophenyl;            difluorophenyl; and monofluorophenyl and        -   the other of R^(5a), R^(5b) and R^(5b1) are selected from            group b): hydrogen, and C₁-C₆alkyl;        -   each R^(5c) is independently hydrogen, or C₁-C₆alkyl and            R^(5d) is hydrogen, or C₁-C₆alkyl; or R^(5c) and R^(5d)            together with the nitrogen to which they are attached form a            3-8 membered saturated ring where the other 2-7 ring members            are carbon;        -   HET1 is C₃-C₈heterocycloalkyl;

    -   wherein, for ring (g),        -   Q¹ is CR^(Q1), Q² is N, and Q³ is 0; or Q¹ is CR^(Q1), Q² is            O, and Q³ is N; or Q¹ is S, Q² is N, and Q³ is N; or Q¹ is            N, Q² is N, and Q³ is 0; or Q¹ is O, Q² is N, and Q³ is N;            where R^(Q1) is hydrogen, C(O)C₁-C₆alkyl, or C₁;        -   R⁶ is a 5- or 6-membered monocyclic heteroaryl substituted            with Q and optionally substituted with R^(2e); or R⁶ is Q;        -   Q is —(CH₂)₀₋₃NR^(6b)C(O)R^(6a),            —(CH₂)₀₋₂NR^(6b)S(O)₂R^(6a), —C(O)R^(6a),            —C(O)NR^(6b)R^(6a), or C₃-C₈heterocycloalkyl substituted            with —C(O)R^(6a);        -   one of R^(6a) and R^(6b) is selected from group a): is            C₁-C₆alkyl substituted with 1 or 2 halo which are            independently selected; C₁-C₆alkyl substituted with cyano;            C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano;            C₂-C₆alkenyl substituted with halo;            —CH═CH—CH₂—NR^(6c)R^(6d); —CH═CH—CH₂—O—C₁-C₆alkyl;            C₃-C₈cycloalkenyl; —C(O)cycloalkyl; alkynyl;            —CH≡CH—CH₂—NR^(6c)R^(6d); CH≡CH—CH₂—OH;            CH≡CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted with            cyano; chloropyridyl, fluoropyridyl, chloropyrazinyl,            fluoropyrazinyl, chloropyrimidinyl, fluoropyrimidinyl,            pentafluorophenyl; tetraflurophenyl; trifluorophenyl;            difluorophenyl; and monofluorophenyl; and        -   the other of R^(6a) and R^(6b) is selected from group b):            hydrogen, and C₁-C₆alkyl;        -   R^(6c) is hydrogen, or C₁-C₆alkyl and R^(6d) is hydrogen, or            C₁-C₆alkyl; or R^(6c) and R^(6d) together with the nitrogen            to which they are attached form a 3-8 membered saturated            ring where the other 2-7 ring members are carbon; and        -   each R⁷ is independently hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy,            or C₃-C₈cycloalkyl;

    -   or a pharmaceutically acceptable salt or salts thereof; and/or a        stereoisomer or mixture of stereoisomers thereof.

In another aspect provided is a compound comprising analkenyl-containing or alkynyl-containing electrophilic group capable ofbinding to KAT6A or KAT6B irreversibly and/or covalently. Also includedare other electrophilic groups like nitrile and halomethyl ketone.

In one aspect, provided is a compound of Formula (I):

-   -   where R¹ is C₃-C₈-cycloalkyl optionally substituted with 1, 2,        or 3 R^(1a); C₃-C₈-cycloalkylalkyl where the C₃-C₈-cycloalkyl is        optionally substituted with 1, 2, or 3 R^(1a); phenyl optionally        substituted with 1, 2, or 3 R^(1b); naphthyl optionally        substituted with 1, 2, or 3 R^(1b); 5- or 6-membered monocyclic        heteroaryl optionally substituted with 1, 2, or 3 R^(1b); or        8-10-membered bicyclic heteroaryl optionally substituted with 1,        2, or 3 R^(1b);    -   each R^(1a) is independently selected from H, halo, C₁-C₆alkoxy,        and C₃-C₈-cycloalkyloxy;    -   each R^(1b) is independently selected from H, halo, C₁-C₆alkoxy,        cyano, and C₃-C₈-cycloalkyloxy;    -   R² is selected from the group consisting of:

-   -   wherein, for ring (a),        -   R^(2b) is hydrogen or C₁-C₆alkyl;        -   one X¹ is C(CH₂R^(2c)), and the other two X¹ are            independently selected from N and CR^(2e);        -   R^(2c) is a 5-membered monocyclic heteroaryl optionally            substituted with 1 or 2 R^(2c1); R^(2c) is a 8- or            9-membered bicyclic heterocyclic optionally substituted with            1 or 2 R^(2c1); R^(2c) is a 6-membered monocyclic heteroaryl            optionally substituted with 1, 2, or 3 R^(2c1); R^(2c) is a            9-membered bicyclic heteroaryl optionally substituted with            1, 2, or 3 R^(2c1); or R^(2c) is a 10-membered bicyclic            heteroaryl optionally substituted with 1, 2, or 3 R^(2c1);            and            -   each R^(2c1) is independently H, halo, C₁-C₆alkyl,                C₁-C₆alkylcarbonyl, —CN, C₁-C₆alkoxy,                C₃-C₈cycloalkyloxy, —(CH₂)₀₋₁NH₂, —NH(C₁-C₆alkyl),                —N(C₁-C₆alkyl)₂, —(CH₂)₀₋₁NHC(O)R^(2f),                —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or 6-membered monocyclic                heteroaryl, or 9- or 10-membered bicyclic heteroaryl;                wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl, or                C₃-C₆cycloalkylC₁-C₃alkyl;    -   wherein, for ring (b),        -   one X¹ is C(CH₂R^(2c)), and the other two X¹ are            independently selected from N and CR^(2e);        -   R^(2c) is a 5-membered monocyclic heteroaryl substituted            with R^(2c2) and optionally substituted with R^(2c3); R^(2e)            is a 8- or 9-membered bicyclic heterocyclic optionally            substituted with 1 or 2 R^(2c1); R² is a 8- or 9-membered            bicyclic heterocyclic substituted with R^(2c2) and            optionally substituted with R^(2c3); R^(2c) is a 6-membered            monocyclic heteroaryl substituted with R^(2c2) and            optionally substituted with 1 or 2 R^(2c3); R^(2c) is a            9-membered bicyclic heteroaryl substituted with R^(2c2) and            optionally substituted with 1 or 2 R^(2c3); or R^(2c) is a            10-membered bicyclic heteroaryl optionally substituted with            1, 2, or 3 R^(2c1);            -   R^(2c2) is hydrogen, C₁-C₆alkylcarbonyl, —CN, —CH₂NH₂,                C₁-C₆alkoxy, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂,                —CH₂NHC(O)R^(2f), —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or                6-membered monocyclic heteroaryl, or 9- or 10-membered                bicyclic heteroaryl; wherein R^(2f) is C₁-C₆alkyl,                C₃-C₆cycloalkyl, or C₃-C₆cycloalkylC₁-C₃alkyl;            -   R^(2c3) is independently H, halo, C₁-C₆alkyl,                C₁-C₆alkoxy, or C₃-C₈cycloalkyloxy; and            -   each R^(2c1) is independently H, halo, C₁-C₆alkyl,                C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, C₃-C₈cycloalkyloxy,                —CN, —CH₂NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂,                —CH₂NHC(O)R^(2f), —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or                6-membered monocyclic heteroaryl, or 9- or 10-membered                bicyclic heteroaryl; wherein R^(2f) is C₁-C₆alkyl,                C₃-C₆cycloalkyl, or C₃-C₆cycloalkylC₁-C₃alkyl;    -   wherein, for ring (c),        -   one X¹ is C(CH₂R^(2c)), and the other two X¹ are            independently selected from N and CR^(2e);

-   -   -   R^(2c) is a 5-membered monocyclic heteroaryl optionally            substituted with 1 or 2 R^(2c1); R^(2c) is a 8- or            9-membered bicyclic heterocyclic optionally substituted with            1 or 2 R^(2c1); R^(2c) is a 6-membered monocyclic heteroaryl            optionally substituted with 1, 2, or 3 R^(2c1); R^(2c) is a            9-membered bicyclic heteroaryl optionally substituted with            1, 2, or 3 R^(2c1); or R², is a 10-membered bicyclic            heteroaryl optionally substituted with 1, 2, or 3 R^(2c1);            and            -   each R^(2c1) is independently H, halo, C₁-C₆alkyl,                C₁-C₆alkylcarbonyl, —CN, C₁-C₆alkoxy,                C₃-C₈cycloalkyloxy, —CH₂NH₂, —NH(C₁-C₆alkyl),                —N(C₁-C₆alkyl)₂, —CH₂NHC(O)R^(2f),                —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or 6-membered monocyclic                heteroaryl, or 9- or 10-membered bicyclic heteroaryl;                wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl, or                C₃-C₆cycloalkylC₁-C₃alkyl;

    -   R^(2d) is halo, C₁-C₆alkyl, C₁-C₆alkoxy, or C₃-C₈-cycloalkyloxy;        and

    -   each R^(2e) is independently hydrogen, halo, C₁-C₃alkyl,        cyclopropyl, —CHF₂, —CF₃, C₁-C₄alkoxy, —OCHF₂, or —OCF₃;

    -   or a pharmaceutically acceptable salt or salts thereof; and/or a        stereoisomer or mixture of stereoisomers thereof.

In another aspect, provided herein is a compound of R²NH₂ (Formula A),where R² is selected from the group consisting of:

-   -   wherein, for ring (a),        -   R^(2b) is hydrogen or C₁-C₆alkyl;        -   one X¹ is C(CH₂R^(2c)), and the other two X¹ are            independently selected from N and CR^(2e);        -   R^(2c) is a 5-membered monocyclic heteroaryl optionally            substituted with 1 or 2 R^(2c1); R^(2c) is a 8- or            9-membered bicyclic heterocyclic optionally substituted with            1 or 2 R^(2c1); R^(2c) is a 6-membered monocyclic heteroaryl            optionally substituted with 1, 2, or 3 R^(2c1); R^(2c) is a            9-membered bicyclic heteroaryl optionally substituted with            1, 2, or 3 R^(2c1); or R^(2c) is a 10-membered bicyclic            heteroaryl optionally substituted with 1, 2, or 3 R^(2c1);            and            -   each R^(2c1) is independently H, halo, C₁-C₆alkyl,                C₁-C₆alkylcarbonyl, —CN, C₁-C₆alkoxy,                C₃-C₈cycloalkyloxy, —(CH₂)₀₋₁NH₂, —NH(C₁-C₆alkyl),                —N(C₁-C₆alkyl)₂, —(CH₂)₀₋₁NHC(O)R^(2f),                —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or 6-membered monocyclic                heteroaryl, or 9- or 10-membered bicyclic heteroaryl;                wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl, or                C₃-C₆cycloalkylC₁-C₃alkyl;    -   wherein, for ring (b),        -   one X¹ is C(CH₂R^(2c)), and the other two X¹ are            independently selected from N and CR^(2e);        -   R^(2c) is a 5-membered monocyclic heteroaryl substituted            with R^(2c2) and optionally substituted with R^(2c3); R^(2c)            is a 8- or 9-membered bicyclic heterocyclic optionally            substituted with 1 or 2 R^(2c1); R^(2c) is a 6-membered            monocyclic heteroaryl substituted with R^(2c2) and            optionally substituted with 1 or 2 R^(2c3); R^(2c) is a            9-membered bicyclic heteroaryl substituted with R^(2c2) and            optionally substituted with 1 or 2 R^(2c3); or R^(2c) is a            10-membered bicyclic heteroaryl optionally substituted with            1, 2, or 3 R^(2c1);            -   R^(2c2) is C₁-C₆alkylcarbonyl, —CN, —(CH₂)₀₋₁NH₂,                C₁-C₆alkoxy, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂,                —(CH₂)₀₋₁NHC(O)R^(2f), —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or                6-membered monocyclic heteroaryl, or 9- or 10-membered                bicyclic heteroaryl; wherein R^(2f) is C₁-C₆alkyl,                C₃-C₆cycloalkyl, or C₃-C₆cycloalkylC₁-C₃alkyl;            -   R^(2c3) is independently H, halo, C₁-C₆alkyl,                C₁-C₆alkoxy, or C₃-C₈cycloalkyloxy; and            -   each R^(2c1) is independently H, halo, C₁-C₆alkyl,                C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, C₃-C₈cycloalkyloxy,                —CN, —(CH₂)₀₋₁NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂,                —(CH₂)₀₋₁NHC(O)R^(2f), —(CH₂)₀₋₁NHC(O)OR^(2f), 5 or                6-membered monocyclic heteroaryl, or 9- or 10-membered                bicyclic heteroaryl; wherein R^(2f) is C₁-C₆alkyl,                C₃-C₆cycloalkyl, or C₃-C₆cycloalkylC₁-C₃alkyl;    -   wherein, for ring (c),        -   one X¹ is C(CH₂R^(2c)), and the other two X¹ are            independently selected from N and CR^(2e);

-   -   -   R^(2c) is a 5-membered monocyclic heteroaryl optionally            substituted with 1 or 2 R^(2c1); R^(2c) is a 8- or            9-membered bicyclic heterocyclic optionally substituted with            1 or 2 R^(2c1); R^(2c) is a 6-membered monocyclic heteroaryl            optionally substituted with 1, 2, or 3 R^(2c1); R^(2c) is a            9-membered bicyclic heteroaryl optionally substituted with            1, 2, or 3 R^(2c1); or R^(2c) is a 10-membered bicyclic            heteroaryl optionally substituted with 1, 2, or 3 R^(2c1);            and            -   each R^(2c1) is independently H, halo, C₁-C₆alkyl,                C₁-C₆alkylcarbonyl, —CN, C₁-C₆alkoxy,                C₃-C₈cycloalkyloxy, —(CH₂)₀₋₁NH₂, —NH(C₁-C₆alkyl),                —N(C₁-C₆alkyl)₂, —(CH₂)₀₋₁NHC(O)R^(2f),                —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or 6-membered monocyclic                heteroaryl, or 9- or 10-membered bicyclic heteroaryl;                wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl, or                C₃-C₆cycloalkylC₁-C₃alkyl;

    -   R^(2d) is halo, C₁-C₆alkyl, C₁-C₆alkoxy, or C₃-C₈-cycloalkyloxy;        and

    -   each R^(2e) is independently hydrogen, halo, C₁-C₃alkyl,        cyclopropyl, CHF₂, CF₃, C₁-C₄alkoxy, —OCHF₂, or —OCF₃;

    -   or a pharmaceutically acceptable salt or salts thereof; and/or a        stereoisomer or mixture of stereoisomers thereof.

In another aspect, provided herein are pharmaceutical compositions,single unit dosage forms, and kits suitable for use in treatingdisorders by inhibiting MYST family of lysine acetyl transferases,including KAT6A and KAT6B, which comprise a therapeutically effectiveamount of a compound provided herein, e.g., of some or any of theembodiments, of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1),(If-1), or (Ig-1), and specific compounds, and a pharmaceuticallyacceptable carrier thereof.

In another aspect, provided herein is a method of treating a condition,disease, or disorder by inhibiting MYST family of lysine acetyltransferases, including KAT6A and KAT6B, comprising a) administering atherapeutically effective amount of a compound provided herein, e.g., ofsome or any of the embodiments, of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2),(Id-1), (Ie-1), (If-1), or (Ig-1), and specific compounds or astereoisomer, a mixture of stereoisomers, and/or a pharmaceuticallyacceptable salt thereof or b) administering a therapeutically effectiveamount of a composition comprising a compound provided herein, e.g., ofsome or any of the embodiments, of Formula (I), (Ia), (Ib), (Ic), (Id),(le), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2),(Id-1), (Ie-1), (If-1), or (Ig-1), and specific compounds or astereoisomer, a mixture of stereoisomers, and/or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrierthereof.

In another aspect, provided herein is a method of preparing a compoundof Formula (I), and specific compounds or a stereoisomer, a mixture ofstereoisomers, and/or a pharmaceutically acceptable salt thereofcomprising treating

-   -   or a salt thereof, where    -   R¹ is C₃-C₈-cycloalkyl optionally substituted with 1, 2, or 3        Ria; C₃-C₈-cycloalkyl-C₁-C_(8alkyl) where the C₃-C₈-cycloalkyl        is optionally substituted with 1, 2, or 3 Ria; phenyl optionally        substituted with 1, 2, or 3 R^(1b); naphthyl optionally        substituted with 1, 2, or 3 R^(1b); or 5- or 6-membered        monocyclic heteroaryl optionally substituted with 1, 2, or 3        R^(1b); 8- to 10-membered bicyclic heteroaryl optionally        substituted with 1, 2, or 3 R^(1b);    -   each R^(1a) is independently selected from hydrogen, halo,        C₁-C₆alkoxy, and C₃-C₈-cycloalkyloxy;    -   each R^(1b) is independently selected from hydrogen, halo,        C₁-C₆alkyl, C₁-C₆alkoxy, hydroxyalkyloxy,        —O-alkylene-NR^(1b1)R^(1b4), —O-alkylene-C(O)OR^(1b1),        —O-alkylene-O-alkylene-NR^(1b1)R^(1b4),

-   -    cyano, —(CH₂)₀₋₂C(O)OR^(1b1), —(CH₂)₀₋₂C(O)NR^(1b2)R^(1b3),        —(CH₂)₀₋₂NRC(O)R, —(CH₂)₀₋₂OH, and C₃-C₈-cycloalkyloxy;    -   R^(1b1) is hydrogen or C₁-C₆alkyl; R^(1b2) is hydrogen or        C₁-C₆alkyl; R^(1b3) is hydrogen or C₁-C₆alkyl; and R^(1b4) is        hydrogen,

-   -   a) where R^(2x) is

-   -    and        -   R^(2a) is hydrogen or C₁-C₆alkyl;        -   each R^(2b) is independently hydrogen, halo, C₁-C₃alkyl,            —(CH₂)₀₋₂OH, cyclopropyl, cyano, —CHF₂, —CF₃, C₁-C₄alkoxy,            —OCHF₂, —OCF₃, or C₃-C₈cycloalkyloxy;        -   each R^(2e) is independently hydrogen, —OH, halo,            C₁-C₆alkyl, halo-C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆alkoxy,            halo-C₁-C₆alkoxy, or C₃-C₈cycloalkyloxy;

-   -   -   one X¹ is CR³ and the other X¹ are independently selected            from N and CR^(2b);        -   R^(2d) is hydrogen, halo, C₁-C₆alkyl, C₁₋₆cycloalkyl,            C₁-C₆alkoxy, or C₃-C₈-cycloalkyloxy;        -   R³ is —(CH₂)₀₋₂Y^(x) or —(CH₂)₀₋₂-L-Y^(x);        -   L is —L¹—L²—L³—, where L¹, L² and L³ are each independently            a bond, —CRR—, O, S(O)₀₋₂, C(O) or NR, where each R is            independently H or alkyl; and        -   Y^(x) is a 5-membered monocyclic heteroaryl optionally            substituted with R^(2e); Y^(x) is an 8-membered bicyclic            heteroaryl optionally substituted with 1 or 2 R^(2e); Y^(x)            is a 9-membered bicyclic heteroaryl optionally substituted            with 1, 2, or 3 R^(2e); Y^(x) is a 10-membered bicyclic            heteroaryl optionally substituted with 1, 2, or 3 R^(2e);            Y^(x) is a 8- or 9-membered bicyclic heterocyclic optionally            substituted with 1 or 2 R^(2e); Y^(x) is a 4-9-membered            monocyclic or bicyclic heterocycloalkyl optionally            substituted with 1 or 2 R^(2e); or Y^(x) is

-   -   -   a1) wherein Y has a substitutable nitrogen comprised as a            ring atom in the 5-membered monocyclic heteroaryl,            8-membered bicyclic heteroaryl, 9-membered bicyclic            heteroaryl, 10-membered bicyclic heteroaryl, and 8- or            9-membered bicyclic heterocyclic; or        -   a2) wherein Y is substituted with —(CH₂)₀₋₂—NH₂, or            —(CH₂)₀₋₂—NH—(C₁-C₆alkylene)NH₂; wherein the group in al) is            treated with an intermediate of formula LG-C(O)R^(3a); or            wherein the group in a2) is treated with an intermediate of            formula LG-C(O)R^(3a), LG-S(O)₂R^(3a);            LG-C(O)(C₁-C₆alkylene)NR^(3b)C(O)R^(3a),            LG-C(O)(C₁-C₆alkylene)NR^(3b)S(O)₂R^(3a), where            -   LG is a leaving group such as halo or OH activated with                a reagent such as HATU, HBTU, T3P, EDCI/HOBt or other                agents known to those skilled in the art;            -   one of R^(3a) and R^(3b) is selected from group a):                C₁-C₆alkyl substituted with 1 or 2 halo which are                independently selected; C₁-C₆alkyl substituted with                cyano; C₁-C₆alkyl substituted with fluoroalkoxy;                C₁-C₆alkyl substituted with aryloxy or heteroaryloxy,                each of which may be further substituted with 1-3                substituents each independently selected from halo,                C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, cyano,                C₃-8cycloalkyl or C₃-8heterocycloalkyl; C₂-C₆alkenyl;                C₂-C₆alkenyl substituted with cyano; C₂-C₆alkenyl                substituted with halo; —CH═CH—CH₂—NR^(3c)R^(3d);                —CH═CH—CH₂—O—C₁-C₆alkyl; C₃-C₈cycloalkenyl;                —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;                —CH≡CH—CH₂—NR^(3c)R^(3d); —CH≡CH—CH₂—O—C₁-C₆alkyl;                —CH≡CH—CH₂—O—C₁-C₆alkyl; chloropyridyl, fluoropyridyl,                chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl,                fluoropyrimidinyl, pentafluorophenyl; tetraflurophenyl;                trifluorophenyl; difluorophenyl; and monofluorophenyl;                and            -   the other of R^(3a) and R^(3b) is selected from group                b): hydrogen, and C₁-C₆alkyl;            -   R^(3c) is hydrogen, or C₁-C₆alkyl, and R^(3d) is                hydrogen, or C₁-C₆alkyl; or R^(3c) and R^(3d) together                with the nitrogen to which they are attached form a 3-8                membered, saturated ring where the other 2-7 ring                members are carbon; or

    -   b) where R^(2x) is

-   -    and        -   each R^(2b) is independently hydrogen, halo, C₁-C₃alkyl,            —(CH₂)₀₋₂OH, cyclopropyl, cyano, —CHF₂, —CF₃, C₁-C₄alkoxy,            —OCHF₂, —OCF₃, or C₃-C₈cycloalkyloxy;        -   each R^(2e) is independently hydrogen, halo, —OH,            C₁-C₆alkyl, halo-C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆alkoxy,            halo-C₁-C₆alkoxy, or C₃-C₈cycloalkyloxy;        -   X^(2a) is O or S;        -   one X² is CR^(4x) and the other X² are independently            selected from N and CR²b; and        -   b1) R^(4x) is —(CH₂)₀₋₂HET2; R^(4x) is —C(O)—HET1; R^(4x) is            —(CH₂)₀₋₃NR^(4b)C(O)-HET1; or R^(4x) is            C₃-C₈heterocycloalkyl; and wherein HET2 is a 8-, 9- or            10-membered bicyclic heterocyclic optionally substituted            with 1 or 2 R^(2e) and has a substitutable nitrogen            comprised as a ring atom and HET1 is C₃-C₈heterocycloalkyl            and comprises a substitutable nitrogen as a ring atom in            HET1;        -   b2) R^(4x) is —(CH₂)₀₋₂NH₂; R^(4x) is            —NR^(4b)(C₁-C₆alkylene)NH₂; R^(4x) is            —(CH₂)₀₋₃NR^(4b)C(O)(C₁-C₆alkylene)NH₂; R^(4x) is            —C(O)NR^(4b)(C₁-C₆alkylene)NH₂; or R^(4x) is —C(O)—HET1-NH₂;    -   wherein the group in b1) is treated with an intermediate of        formula LG-C(O)R^(4a); or    -   wherein the group in b2) is treated with an intermediate of        formula LG-C(O)R^(4a) or LG-S(O)₂R^(4a); and    -   where        -   LG is a leaving group such as halo or OH activated with a            reagent such as HATU, HBTU, T3P, EDCI/HOBt or other agents            known to those skilled in the art;        -   R^(4a) is alkyl substituted with 1 or 2 halo which are            independently selected; C₁-C₆alkyl substituted with cyano;            C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano;            C₂-C₆alkenyl substituted with halo;            —CH═CH—CH₂—NR^(4c)R^(4d); —CH═CH—CH₂—O—C₁-C₆alkyl;            C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;            —CH≡CH—CH₂—NR^(4c)R^(4d); CH≡CH—CH₂—OH;            CH≡CH—CH₂—O—C₁-C₆alkyl; chloropyridyl, fluoropyridyl,            chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl,            fluoropyrimidinyl, pentafluorophenyl; tetraflurophenyl;            trifluorophenyl; difluorophenyl; or monofluorophenyl;        -   R^(4b) is hydrogen, or C₁-C₆alkyl;        -   R^(4c) is hydrogen, or C₁-C₆alkyl, and R^(4d) is hydrogen,            or C₁-C₆alkyl; or R^(4c) and R^(4d) together with the            nitrogen to which they are attached form a 3-8 membered,            saturated ring where the other 2-7 ring members are carbon;    -   c) where R^(2x) is

-   -    and        -   each R^(2b) is independently hydrogen, halo, C₁-C₃alkyl,            —(CH₂)₀₋₂OH, cyclopropyl, cyano, —CHF₂, —CF₃, C₁-C₄alkoxy,            —OCHF₂, —OCF₃, or C₃-C₈cycloalkyloxy;        -   R^(5x) is a 5-membered monocyclic heteroaryl substituted            with Z^(x) and optionally substituted with R^(2e); R^(5x) is            a 6-membered monocyclic heteroaryl substituted with Z^(x)            and optionally substituted with R^(2e); R^(5x) is —C(O)LG¹;            R^(5x) is —(CH₂)₀₋₂O-HET1; or R^(5x) is            —(CH₂)₀₋₂O—(CH₂)₀₋₃NH₂; where LG¹ is a leaving group such as            halo or OH activated with a reagent such as HATU, HBTU, T3P,            EDCI/HOBt or other agents known to those skilled in the art;        -   c1) Z^(x) is —(CH₂)₀₋₃NH₂; or Z^(x) is            —(CH₂)₀₋₃NR⁵b(C₁-C₆alkylene)NH₂;        -   c2) Z^(x) is C₃-C₈heterocycloalkyl and comprises a            substitutable nitrogen as a ring atom;    -   wherein the group in c1) is treated with an intermediate of        formula LG²—C(O)R^(5a) or LG²—S(O)₂R^(5a);    -   wherein the group in c2) is treated with an intermediate of        formula LG²—C(O)R^(5a); and    -   where        -   LG² is a leaving group such as halo or OH activated with a            reagent such as HATU, HBTU, T3P, EDCI/HOBt or other agents            known to those skilled in the art        -   R^(5a) is C₁-C₆alkyl substituted with 1 or 2 halo which are            independently selected; C₁-C₆alkyl substituted with cyano;            C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano;            C₂-C₆alkenyl substituted with halo;            —CH═CH—CH₂—NR^(5c)R^(5d); —CH═CH—CH₂—O—C₁-C₆alkyl;            C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;            —CH≡CH—CH₂—NR^(5c)R^(5d); CH≡CH—CH₂—OH;            CH≡CH—CH₂—O—C₁-C₆alkyl; chloropyridyl; fluoropyridyl;            chloropyrazinyl, fluoropyrazinyl, chloropyrimidinyl,            fluoropyrimidinyl, pentafluorophenyl; tetraflurophenyl;            trifluorophenyl; difluorophenyl; or monofluorophenyl; and        -   R^(5b) is hydrogen, or C₁-C₆alkyl;        -   each R^(5c) is independently hydrogen, or C₁-C₆alkyl and            R^(5d) is hydrogen, or C₁-C₆alkyl; or R^(5c) and R^(5d)            together with the nitrogen to which they are attached form a            3-8 membered saturated ring where the other 2-7 ring members            are carbon;    -   to yield a Compound of Formula (I) and specific compounds; or a        stereoisomer, a mixture of stereoisomers, and/or a        pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of preparing a compoundof Formula (I), (Ih), (Ii) and (Ij), and specific compounds or astereoisomer, a mixture of stereoisomers, and/or a pharmaceuticallyacceptable salt thereof comprising treating R²NH₂ (Formula A) withR¹S(O)₂X where X is halo, preferably chloro using coupling conditionsdescribed herein or known to one of ordinary skill in the art. In someor any embodiments, halo is bromo.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows results of a test for reversibility/irreversibility forcompounds provided herein (see, Biological Example 2).

DESCRIPTION OF EXEMPLARY EMBODIMENTS Definitions

When referring to the compounds provided herein, the following termshave the following meanings unless indicated otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of ordinary skill in the art.In the event that there is a plurality of definitions for a term herein,those in this section prevail unless stated otherwise. Unless specifiedotherwise, where a term is defined as being unsubstituted orsubstituted, the groups in the list of substituents are themselvesunsubstituted. For example, a substituted alkyl group can besubstituted, for example, with a cycloalkyl group, and the cycloalkylgroup is not further substituted unless specified otherwise.

Reference to “about” a value or parameter herein includes (anddescribes) variations that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

As used herein, and unless otherwise specified, the terms “about” and“approximately,” when used in connection with temperatures, doses,amounts, or weight percent of ingredients of a composition or a dosageform, mean a dose, amount, or weight percent that is recognized by thoseof ordinary skill in the art to provide a pharmacological effectequivalent to that obtained from the specified dose, amount, or weightpercent. Specifically, the terms “about” and “approximately,” when usedin this context, contemplate a dose, amount, or weight percent within15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1%,or within 0.5% of the specified dose, amount, or weight percent.

The terms “a” or “an,” as used in herein means one or more, unlesscontext clearly dictates otherwise.

“Alkyl” means a linear or branched hydrocarbon group having one to eightcarbon atoms. “Lower alkyl” or “C₁-C₆alkyl” means an alkyl group havingone to six carbon atoms. In some embodiments, lower alkyl includesmethyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl,pentyl, hexyl and the like. A “C₀” alkyl (as in “C₀-C₆-alkyl”) is acovalent bond. “C₆ alkyl” refers to, for example, n-hexyl, iso-hexyl,and the like.

“Alkoxy” means an —OR group where R is an alkyl group as defined herein.In some embodiments, R is C₁-C₆alkyl.

“Alkyloxyalkyl” means an alkyl group, as defined herein, substitutedwith one alkoxy, as defined herein. In some embodiments, alkyloxyalkylis —CH₂OCH₃.

“Alkenyl” means a straight or branched hydrocarbon radical having from 2to 8 carbon atoms and at least one double bond and includes ethenyl,propen-1-yl, propen-2-yl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl andthe like. “Lower alkenyl” means an alkenyl group having two to sixcarbon atoms.

“Alkynyl” means a straight or branched hydrocarbon radical having from 2to 8 carbon atoms and at least one triple bond and includes ethynyl,propynyl, butynyl, pentyn-2-yl and the like. “Lower alkynyl” means analkynyl group having two to six carbon atoms.

“Cycloalkyl” means a monocyclic or polycyclic hydrocarbon radical havingthree to thirteen carbon atoms. The cycloalkyl can be saturated orpartially unsaturated, but cannot contain an aromatic ring. In someembodiments, cycloalkyl is C₃-C₈cycloalkyl. In some embodiments,cycloalkyl is C₃-C₆cycloalkyl. In some embodiments, cycloalkyl includesfused, bridged, and spiro ring systems. In some embodiments, cycloalkylis cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

“Cycloalkylalkyl” means alkyl group substituted with one or twocycloalkyl group(s), as defined herein. In some embodiments,cycloalkylalkyl includes cyclopropylmethyl, 2-cyclobutyl-ethyl, and thelike.

“Spirocycloalkyl substituted with cyano” means

In some embodiments, spirocycloalkyl substituted with cyano is

In some embodiments, spirocycloalkyl substituted with cyano is

In some embodiments, spirocycloalkyl substituted with cyano is

“Cycloalkyloxy” means an —OR group where R is cycloalkyl, as definedherein.

“Cycloalkenyl” means a cycloalkyl, as defined herein, which comprises atleast one double bond, but wherein the ring is not aromatic.

“Haloalkyl” means an alkyl group, as defined herein, substituted withone or more halogens, for example one, two, three, four, or five haloatoms. Representative examples includes 2,2-difluoroethyl,trifluoromethyl, and 2-chloro-1-fluoroethyl, and the like.

“Haloalkoxy” means an —OR′ group where R′ is haloalkyl as definedherein, in some embodiments, haloalkoxy is trifluoromethoxy or2,2,2-trifluoroethoxy, and the like.

“Heteroaryl” means a monocyclic or bicyclic, monovalent aromatic radicalof 5-10 ring atoms containing one or more heteroatoms, for example one,two, or three ring heteroatoms, independently selected from oxygen,nitrogen, and sulfur and the remaining ring atoms being carbon. Unlessstated otherwise, the point of attachment may be located on any atom ofany ring of the heteroaryl group, valency rules permitting. In someembodiments, the term heteroaryl includes, but is not limited to,1,2,4-triazolyl, 1,3,5-triazolyl, pyrrolyl, imidazolyl, thienyl,furanyl, tetrazoyl, pyridinyl, pyrazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, indolyl, isoindolyl, benzothiazolyl,benzoxazolyl, quinolinyl, isoquinolinyl, tetrazolyl, and the like, andan N-oxide thereof. When the heteroaryl ring contains 5 or 6 ring atoms,it is also referred to herein as 5- or 6-membered heteroaryl.“Heteroaryl” also includes “8-10-membered bicyclic heteroaryl,” as usedherein.

“Heterocycloalkyl,” as used herein, means a saturated or partiallyunsaturated (but not aromatic) monovalent monocyclic group of 3 to 9ring atoms or a saturated or partially unsaturated (but not aromatic)monovalent fused bicyclic group of 5 to 12 ring atoms in which one ormore heteroatoms, for example one, two, three, or four ring heteroatoms,independently selected from —O—, —S(O)_(n)— (n is 0, 1, or 2), —N═,—N(R^(y))— (where R^(y) is a substituent as provided in any embodimentfor a heterocycloalkyl, including for example —C(O)R^(4a) and similargroups), the remaining ring atoms being carbon. One or two ring carbonatoms may be replaced by a —C(O)—, —C(S)—, or —C(═NH)— group. Fusedbicyclic radical includes bridged ring systems and spirocyclic ringsystems. Unless otherwise stated, the point of attachment of the groupmay be located on any atom of any ring within the radical, valency rulespermitting. In particular, when the point of attachment is located on anitrogen atom, R^(y) is absent. More specifically the termheterocycloalkyl includes, but is not limited to, azetidinyl,pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dihydro-1H-pyrrolyl, piperidinyl,4-piperidonyl, morpholinyl, piperazinyl, 2-oxopiperazinyl,tetrahydropyranyl, 2-oxopiperidinyl, thiomorpholinyl, thiamorpholinyl,perhydroazepinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,dihydropyridinyl, tetrahydropyridinyl, oxazolinyl, oxazolidinyl,isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl,isothiazolidinyl, octahydroindolyl, octahydroisoindolyl,decahydroisoquinolyl, tetrahydrofuryl, octahydropyrrolo[3,4-c]pyrrolyl,(3aR,6aS)-hexahydro-1H-5λ²-pyrrolo[3,4-c]pyrrolyl, andtetrahydropyranyl, and an N-oxide thereof.

“Bicyclic heterocyclic,” as used herein, and unless otherwise specified,refers to a bicyclic ring system that contains one non-aromatic ring andone aromatic ring; wherein one or more (in some or any embodiments, 1,2, 3, or 4) of any of the ring atoms in the bicyclic ring system is aheteroatom(s) independently selected from O, S(O)₀₋₂, and N, and theremaining ring atoms are carbon, and wherein the bicyclic heterocycliccontains 8-12 ring atoms (in some embodiments, 8, 9, or 10 ring atoms).The term “bicyclic heterocyclic” does not include a fully aromaticbicyclic ring, i.e. does not include benzisoxazole, indazole, and thelike. In some or any embodiments, the bicyclic heterocyclic group has 8ring atoms. In some or any embodiments, the bicyclic heterocyclic grouphas 9 ring atoms. In some or any embodiments, the bicyclic heterocyclicring comprises one, two, or three heteroatom(s) which are independentlyselected from nitrogen and oxygen. In some or any embodiments, thebicyclic heterocyclic ring comprises one or two heteroatom(s) which areoxygen. In some or any embodiments, the bicyclic heterocyclic ringcomprises one, two, or three heteroatom(s) which are nitrogen (where thenitrogen can be substituted as described in any aspect or embodimentdescribed herein). In some or any embodiments, the bicyclic heterocycliccomprises one heteroatom in the non-aromatic ring, or comprises one ortwo heteroatoms in the aromatic ring, or comprises two heteroatoms inthe aromatic ring, or comprises two heteroatoms where one is in anaromatic ring and the other is in a non-aromatic ring or comprises twoheteroatoms in the aromatic ring and one heteroatom in the nonaromaticring. In some or any embodiments, the bicyclic heterocyclic group may bea bridged or non-bridged, and/or fused or not fused bicyclic group. Oneor more of the nitrogen and sulfur atoms may be optionally oxidized, oneor more of the nitrogen atoms may be optionally quaternized, one or moreof the carbon atoms may be optionally replaced with

The bicyclic heterocyclic may be attached to the main structure at anyheteroatom or carbon atom which results in a stable compound. Thebicyclic heterocyclic may be attached to the main structure through anyof its rings, including any aromatic or nonaromatic ring, regardless ofwhether the ring contains a heteroatom. In some or any embodiments, thebicyclic heterocyclic includes a 5-membered heteroaryl group, preferablypyrazolyl, fused to a nonaromatic ring, preferably comprising a nitrogenring atom, e.g. 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl,4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridinyl, or4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinyl; in some or anyembodiments, the rest of the Compound of Formula (I) is attached to the5-membered heteroaryl group (preferably pyrazolyl), fused to anonaromatic ring (preferably comprising a nitrogen ring atom), throughthe 5-membered heteroaryl portion, e.g.2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-1-yl,2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl,4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-1-yl,4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridin-2-yl,4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-1-yl, or4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl. When the bicyclicheterocyclic is substituted, it can be substituted on any ring, i.e. onany aromatic or nonaromatic ring comprised by the bicyclic heterocyclic.In some or any embodiments, the bicyclic heterocyclic includes, but isnot limited to, 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl,benzodioxolyl, 1,3-dihydroisobenzofuranyl, benzofuranonyl,dihydrobenzofuranyl, benzotetrahydrothienyl,2,2-dioxo-1,3-dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl,indolinyl, 2-oxo-indolinyl, isobenzotetrahydrofuranyl,isobenzotetrahydrothienyl, isoindolinyl, 1-oxo-isoindolinyl,1,3-dioxo-isoindolinyl; each of which is optionally substituted with 1,2, 3, or 4 groups as defined throughout the specification.

“Hydroxyalkyl,” as used herein, and unless otherwise specified, refersto an alkyl group, as defined herein, substituted with 1, 2, or 3hydroxy groups (provided that more than one hydroxy group is not on thesame carbon). In some embodiments, hydroxyalkyl is hydroxyC₁₋₆-alkyl. Insome embodiments, hydroxyalkyl is hydroxyethyl.

“Hydroxyalkyloxy,” as used herein, and unless otherwise specified,refers to an —OR group where R is hydroxylalkyl, as defined herein. Insome embodiments, hydroxyalkyloxy is hydroxyethyloxy.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. It is understood thatthe pharmaceutically acceptable salts are non-toxic. Additionalinformation on suitable pharmaceutically acceptable salts can be foundin Remington's Pharmaceutical Sciences, 17^(th) ed., Mack PublishingCompany, Easton, P A, 1985, which is incorporated herein by reference orS. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977;66:1-19 both of which are incorporated herein by reference. It is alsounderstood that the compound can have one or more pharmaceuticallyacceptable salts associated with it.

Examples of pharmaceutically acceptable acid addition salts includethose formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, and the like; as wellas organic acids such as acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, p-toluenesulfonic acid, and salicylicacid and the like.

Examples of a pharmaceutically acceptable base addition salts includethose formed when an acidic proton present in the parent compound isreplaced by a metal ion, such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Preferable salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins. Examples of organic bases include isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, tromethamine, N-methylglucamine, polyamine resins,and the like. Exemplary organic bases are isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

The term “substantially free of” or “substantially in the absence of”stereoisomers with respect to a composition refers to a composition thatincludes at least 85 or 90% by weight, in certain embodiments 95%, 98%,99% or 100% by weight, of a designated stereoisomer of a compound in thecomposition. In certain embodiments, in the methods and compoundsprovided herein, the compounds are substantially free of stereoisomers.

Similarly, the term “isolated” with respect to a composition refers to acomposition that includes at least 85, 90%, 95%, 98%, 99% to 100% byweight, of a specified compound, the remainder comprising other chemicalspecies or stereoisomers.

The term “solvate,” as used herein, and unless otherwise specified,refers to a compound provided herein or a salt thereof, that furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

The term “isotopic composition,” as used herein, and unless otherwisespecified, refers to the amount of each isotope present for a givenatom, and “natural isotopic composition” refers to the naturallyoccurring isotopic composition or abundance for a given atom. Atomscontaining their natural isotopic composition may also be referred toherein as “non-enriched” atoms. Unless otherwise designated, the atomsof the compounds recited herein are meant to represent any stableisotope of that atom. For example, unless otherwise stated, when aposition is designated specifically as “H” or “hydrogen,” the positionis understood to have hydrogen at its natural isotopic composition.

The term “isotopic enrichment,” as used herein, and unless otherwisespecified, refers to the percentage of incorporation of an amount of aspecific isotope at a given atom in a molecule in the place of thatatom's natural isotopic abundance. In certain embodiments, deuteriumenrichment of 1% at a given position means that 1% of the molecules in agiven sample contain deuterium at the specified position. Because thenaturally occurring distribution of deuterium is about 0.0156%,deuterium enrichment at any position in a compound synthesized usingnon-enriched starting materials is about 0.0156%. The isotopicenrichment of the compounds provided herein can be determined usingconventional analytical methods known to one of ordinary skill in theart, including mass spectrometry and nuclear magnetic resonancespectroscopy.

The term “isotopically enriched,” as used herein, and unless otherwisespecified, refers to an atom having an isotopic composition other thanthe natural isotopic composition of that atom. “Isotopically enriched”may also refer to a compound containing at least one atom having anisotopic composition other than the natural isotopic composition of thatatom.

As used herein, “alkyl,” “cycloalkyl,” and “heterocycloalkyl” groupsoptionally comprise deuterium at one or more positions where hydrogenatoms are present, and wherein the deuterium composition of the atom oratoms is other than the natural isotopic composition.

Also as used herein, “alkyl,” “cycloalkyl,” and “heterocycloalkyl”groups optionally comprise carbon-13 at an amount other than the naturalisotopic composition.

As used herein, and unless otherwise specified, the term “IC₅₀” refersto an amount, concentration or dosage of a particular test compound thatachieves a 50% inhibition of a maximal response in an assay thatmeasures such response.

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “subjects” refer to an animal,such as a mammal including a non-primate (e.g., a cow, pig, horse, cat,dog, rat, and mouse) and a primate (e.g., a monkey such as a cynomolgousmonkey, a chimpanzee and a human), and in certain embodiments, a human.In certain embodiments, the subject is a farm animal (e.g., a horse, acow, a pig, etc.) or a pet (e.g., a dog or a cat). In certainembodiments, the subject is a human.

“Administration” and variants thereof (in some embodiments,“administering” a compound) in reference to a compound of the inventionmeans introducing the compound or a prodrug of the compound into thesystem of the animal in need of treatment. When a compound of theinvention or prodrug thereof is provided in combination with one or moreother active agents (in some embodiments, surgery, radiation, andchemotherapy, etc.), “administration” and its variants are eachunderstood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

“Therapeutically effective amount” is an amount of a compound orcomposition, that when administered to a patient, is sufficient toeffect such treatment for the condition, disease, or disorder, e.g. toameliorate a symptom of the disease. The amount of a compound of theinvention which constitutes a “therapeutically effective amount” willvary depending on the compound, the disease state and its severity, theage of the patient to be treated, and the like. The therapeuticallyeffective amount can be determined routinely by one of ordinary skill inthe art having regard to their knowledge and to this disclosure.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent(s) which can be used in the treatment or preventionof a disorder or one or more symptoms thereof. In certain embodiments,the term “therapeutic agent” includes a compound provided herein. Incertain embodiments, a therapeutic agent is an agent which is known tobe useful for, or has been or is currently being used for the treatmentor prevention of a disorder or one or more symptoms thereof.

“Treating” or “treatment” of a disease, disorder, or syndrome, as usedherein, includes (i) preventing the disease, disorder, or syndrome fromoccurring in a human, i.e. causing the clinical symptoms of the disease,disorder, or syndrome not to develop in an animal that may be exposed toor predisposed to the disease, disorder, or syndrome but does not yetexperience or display symptoms of the disease, disorder, or syndrome;(ii) inhibiting the disease, disorder, or syndrome, i.e., arresting itsdevelopment (stable disease); and (iii) relieving the disease, disorder,or syndrome, e.g. relieving or reducing a symptom thereof, and/orcausing regression of the disease, disorder, or syndrome. As is known inthe art, adjustments for systemic versus localized delivery, age, bodyweight, general health, sex, diet, time of administration, druginteraction and the severity of the condition, disease, or disorder maybe necessary, and will be ascertainable with routine experimentation byone of ordinary skill in the art. “Treating” or “treatment” of anycondition, disease, or disorder refers, in certain embodiments, toameliorating a condition, disease, or disorder that exists in a subject.In another embodiment, “treating” or “treatment” includes amelioratingat least one physical parameter, which may be indiscernible by thesubject. In yet another embodiment, “treating” or “treatment” includesmodulating the condition, disease, or disorder, either physically (e.g.,stabilization of a discernible symptom) or physiologically (e.g.,stabilization of a physical parameter) or both. In yet anotherembodiment, “treating” or “treatment” includes delaying the onset of thecondition, disease, or disorder.

The terms “inhibiting” and “reducing,” or any variation of these termsincludes any measurable decrease or complete inhibition to achieve adesired result. For example, there may be a decrease of about, at mostabout, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or anyrange derivable therein, reduction of the activity compared to normal.

As used herein, the terms “prophylactic agent” and “prophylactic agents”refer to any agent(s) which can be used in the prevention of acondition, disease, or disorder or one or more symptoms thereof. Incertain embodiments, the term “prophylactic agent” includes a compoundprovided herein. In certain other embodiments, the term “prophylacticagent” does not refer a compound provided herein. In certainembodiments, a prophylactic agent can be an agent which is known to beuseful for, or has been or is currently being used to prevent or impedethe onset, development, progression and/or severity of a condition,disease, or disorder.

As used herein, the phrase “prophylactically effective amount” refers tothe amount of a therapy (e.g., prophylactic agent) which is sufficientto result in the prevention or reduction of the development, recurrenceor onset of one or more symptoms associated with a condition, disease,or disorder, or to enhance or improve the prophylactic effect(s) ofanother therapy (e.g., another prophylactic agent).

Compounds

The embodiments described herein include the recited compounds as wellas a pharmaceutically acceptable salt or salts, hydrate, solvate,stereoisomer, tautomer, or mixture thereof.

In some or any embodiments, the compound is according to Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1),(Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1). In some orany embodiments, the pharmaceutical composition comprises a compoundaccording to Formula (I), (Ia), (Ib), (Ic), (Id), (le), (If), (Ig),(Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1),(If-1), or (Ig-1). In some or any embodiments, the method of treatingcomprises administering a compound according to Formula (I), (Ia), (Ib),(Ic), (Id), (le), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1),(Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1).

Embodiment A: In some or any embodiments, the Compound is that wherein

-   -   R¹ is C₃-C₈-cycloalkyl-C₁-C₆alkyl; or phenyl optionally        substituted with 1, 2, or 3 R^(1b);    -   each R^(1b) is independently selected from hydrogen, alkyl,        —C(O)OH, —C(O)O(C₁₋₃alkyl), halo, and C₁-C₆alkoxy;    -   R² is selected from the group consisting of:

-   -   R^(2a) is hydrogen;    -   each R^(2b) is independently hydrogen, C₁-C₃alkyl or        —(CH₂)₀₋₂OH;    -   each R^(2e) is hydrogen;    -   wherein, for rings (a) and (b)        -   one X¹ is CR³ and the other X¹ are each CH;        -   R^(2d) is C₁-C₃alkoxy;        -   R³ is —(CH₂)₀₋₂Y or —(CH₂)₀₋₂—L—Y;        -   L is —L¹—L²—L³—, where L¹, L² and L³ are each independently            a bond, —CRR—, O, S(O)₀₋₂, C(O) or NR, where each R is            independently H or alkyl;        -   Y is a 5-membered monocyclic heteroaryl substituted with            R^(Y); Y is a 8- or 9-membered bicyclic heterocyclic            substituted with R^(Y); or Y is a 4-9-membered monocyclic or            bicyclic heterocycloalkyl substituted with R^(Y) and            optionally substituted with 1 or 2 R^(2e).        -   R^(Y) is —(CH₂)₀₋₃NR^(3b)C(O)R^(3a),            —(CH₂)₀₋₂NR^(3b)S(O)₂R^(3a), —C(O)R^(3a), —S(O)₂R^(3a),            —C(O)NR^(3b)R^(3a), or C₃-C₈heterocycloalkyl substituted            with —C(O)R^(3a);        -   R^(3a) is C₁-C₆alkyl substituted with 1 or 2 halo;            C₁-C₆alkyl substituted with fluoroalkoxy; C₁-C₆alkyl            substituted with aryloxy or heteroaryloxy, each of which may            be further substituted with 1-3 substituents each            independently selected from halo, C₁₋₆alkyl, C₂₋₆alkenyl,            C₁₋₆alkoxy, cyano, C₃₋₈cycloalkyl or C₃₋₈heterocycloalkyl;            C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano;            C₂-C₆alkenyl substituted with halo;            —CH═CH—CH₂—NR^(3c)R^(3d); —CH═CH—CH₂—O—C₁-C₆alkyl;            tetrafluorophenyl; trifluorophenyl; C₂-C₆alkynyl; or            —CH≡CH—CH₂—NR^(3c)R^(3d);        -   R^(3b) and R^(3b1) are each independently hydrogen or            C₁-C₆alkyl; and        -   R^(3c) is hydrogen or C₁-C₆alkyl, and R^(3d) is hydrogen or            C₁-C₆alkyl;    -   wherein, for ring (d),        -   X^(2a) is O;        -   one X² is CR⁴ and the other X² are each CH;        -   R⁴ is —(CH₂)₀₋₃NR^(4b)C(O)R^(4a),            —NR^(4b)(C₁-C₆alkylene)NR^(4b1)C(O)R^(4a),            —(CH₂)₀₋₃NR^(4b)C(O)(C₁-C₆alkylene)NR^(4b)C(O)R^(4a),            —C(O)NR^(4b)(C₁-C₆alkylene)NR^(4b)C(O)R^(4a),            —C(O)—HET1—C(O)R^(4a), —C(O)—HET1—NR^(4b)C(O)R^(4a),            —(CH₂)₀₋₃NR^(4b)C(O)-HET1—C(O)R^(4a), C₃-C₈heterocycloalkyl            substituted with —C(O)R^(4a) (preferably where the            C₃-C₈heterocycloalkyl is attached to ring (d) through a            carbon in the C₃-C₈heterocycloalkyl ring); or            —(CH₂)₀₋₂HET2—C(O)R^(4a);        -   R^(4a) is C₂-C₆alkenyl or C₂-C₆alkynyl;        -   R^(4b) and R^(4b1) are each hydrogen;        -   HET1 is C₃-C₈heterocycloalkyl comprising at least one            nitrogen; and        -   HET2 is an 8-, 9- or 10-membered bicyclic heterocyclic            comprising at least one nitrogen ring atom and —C(O)R^(4a)            is to attached to HET2 through the at least one nitrogen            ring atom in the HET2 ring;    -   wherein, for ring (e) and (f),        -   R⁵ is a 5-membered monocyclic heteroaryl substituted with Z            and; or R⁵ is a 6-membered monocyclic heteroaryl substituted            with Z;        -   Z is —(CH₂)₀₋₃NR^(5b)C(O)R^(5a),            —(CH₂)₀₋₃NR⁵b(C₁-C₆alkylene)NR^(5b1)C(O)R^(5a),            C₃-C₈heterocycloalkyl substituted with —S(O)₂R^(5a), or            C₃-C₈heterocycloalkyl substituted with C(O)R^(5a);        -   R^(5a) is C₂-C₆alkenyl or C₂-C₆alkynyl;        -   R^(5b) and R^(5b1) are each hydrogen;    -   wherein, for ring (g),        -   Q¹ is CH, Q² is N, and Q³ is O;        -   R⁶ is a 5-membered monocyclic heteroaryl substituted with Q;            or R⁶ is Q;        -   Q is —(CH₂)₀₋₃NR⁶C(O)R^(6a);        -   R^(6a) is C₂-C₆alkenyl;        -   R^(6b) is hydrogen; and        -   each R⁷ is independently hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy,            or C₃-C₈cycloalkyl;    -   or a pharmaceutically acceptable salt or salts thereof; and/or a        stereoisomer or mixture of stereoisomers thereof.

Embodiment 1: Provided is a compound according to Formula (I), whereinR¹ is C₃-C₈-cycloalkylalkyl where the C₃-C₈-cycloalkylalkyl isoptionally substituted with 1, 2, or 3 Ria, or phenyl optionallysubstituted with 1, 2, or 3 R^(1b); and all other groups are as definedin the Summary or in some or any embodiment provided herein.

Embodiment 2: Provided is a compound according to Formula (I), whereinR¹ is C₃-C₈-cycloalkylalkyl where the C₃-C₈-cycloalkylalkyl isoptionally substituted with 1, 2, or 3 R^(1a); and all other groups areas defined in the Summary or in some or any embodiment provided herein.

Embodiment 3: Provided is a compound according to Formula (I), whereinR¹ is C₃-C₈-cycloalkyl optionally substituted with 1, 2, or 3 R^(1a);and all other groups are as defined in the Summary or in some or anyembodiment provided herein.

Embodiment 4: Provided is a compound according to Formula (I), whereineach R^(1a) is independently hydrogen; and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 1-3.

Embodiment 5: Provided is a compound according to Formula (I), whereinR¹ is phenyl optionally substituted with 1, 2, or 3 R^(1b); and allother groups are as defined in the Summary or in some or any embodimentprovided herein, including Embodiment 1.

Embodiment 6: Provided is a compound according to Formula (I), whereinR¹ is phenyl-C₁-C₆alkyl optionally substituted with 1, 2, or 3 R^(1b);and all other groups are as defined in the Summary or in some or anyembodiment provided herein.

Embodiment 7: Provided is a compound according to Formula (I), whereinR¹ is naphthyl optionally substituted with 1, 2, or 3 R^(1b); and allother groups are as defined in the Summary or in some or any embodimentprovided herein.

Embodiment 8: Provided is a compound according to Formula (I), whereinR¹ is 5- or 6-membered monocyclic heteroaryl optionally substituted with1, 2, or 3 R^(1b); and all other groups are as defined in the Summary orin some or any embodiment provided herein.

Embodiment 9: Provided is a compound according to Formula (I), (whereinR¹ is 8-10-membered bicyclic heteroaryl; and all other groups are asdefined in the Summary or in some or any embodiment provided herein.

Embodiment 10: Provided is a compound according to Formula (I), whereineach R^(1b) is independently selected from hydrogen, halo, C₁-C₆alkyl,C₁-C₆alkoxy, hydroxyC₁₋₆-alkyloxy, —O-alkylene-NR^(1b1)R^(1b4),—O-alkylene-O-alkylene-NR^(1b1)R^(1b4)

—(CH₂)₀₋₂C(O)OR^(1b1), —(CH₂)₀₋₂C(O)NR^(1b2)R^(1b3), and—(CH₂)₀₋₂NR^(1b1)C(O)R^(1b3); and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1 and 5-9. In a subembodiment of embodiment 10, providedis compound of Formula (I), wherein each R^(1b) is independentlyselected from hydrogen, halo, C₁-C₃alkyl, C₁-C₃alkoxy,hydroxyC₁₋₄-alkyloxy, —C(O)OR^(1b1), —C(O)NHR^(1b3), and —NHC(O)R^(1b3).In a subembodiment of embodiment 10, provided is compound of Formula(I), wherein each R^(1b) is independently selected from hydrogen,fluoro, ethyl, methoxy, hydroxyethyloxy, —C(O)OH, —C(O)O CH₃, and—C(O)NHCH₃. In a subembodiment of embodiment 10 and subembodimentsthereof, provided is compound of (I), wherein one or two R^(1b) arepresent. In a subembodiment of embodiment 10 and subembodiments thereof,provided is a compound according to Formula (I), wherein one R^(1b) arepresent. In a subembodiment of embodiment 10 and subembodiments thereof,provided is compound of Formula (I), wherein two R^(1b) are present.

Embodiment 11. Provided is a compound of Formula (I) according toFormula (Ia):

where R¹, R^(2a), R^(2d), and X¹ and all other groups are as defined inthe Summary or in some or any embodiment provided herein, including anyone of Embodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof; and/or a stereoisomer or mixture of stereoisomers thereof. Insome or any embodiments of Embodiment 1, R^(2a) is hydrogen or methyl.In some or any embodiments, provided is a compound of Formula (I)according to Formula (Ia-1):

where R¹, R^(2a), R^(2d), R³, and X¹ and all other groups are as definedin the Summary or in some or any embodiment provided herein, includingany one of Embodiments 1-10; or a pharmaceutically acceptable salt orsalts thereof; and/or a stereoisomer or mixture of stereoisomersthereof. In some or any embodiments of Embodiment 11, provided is acompound of Formula (Ia) or (Ia-1), wherein R^(2a) is hydrogen orC₁-C₃alkyl. In some or any embodiments of Embodiment 11, provided is acompound of Formula (Ia) or (Ia-1), wherein R^(2a) is hydrogen ormethyl. In some or any embodiments of Embodiment 11, provided is acompound of Formula (Ia) or (Ia-1), wherein R^(2a) is hydrogen. In someor any embodiments of Embodiment 11, provided is a compound of Formula(Ia) or (Ia-1), wherein R^(2a) is C₁-C₆alkyl. In some or any embodimentsof Embodiment 11, provided is a compound of Formula (Ia) or (Ia-1),wherein R^(2a) is C₁-C₃alkyl. In some or any embodiments of Embodiment11, provided is a compound of Formula (Ia) or (Ia-1), wherein R^(2a) ismethyl.

Embodiment 12. Provided is a compound of Formula (I) according toFormula (Ib):

where R¹, R^(2d), and X¹ and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof; and/or a stereoisomer or mixture of stereoisomers thereof. Insome or any embodiments, provided is a compound of Formula (I) accordingto Formula (Ib-1):

where R¹, R^(2d), R³, and X¹ and other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof, and/or a stereoisomer or mixture of stereoisomers thereof.

Embodiment 13. Provided is a compound of Formula (I) according toFormula (Ic):

where R¹, R^(2d), X¹,

and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10; or apharmaceutically acceptable salt or salts thereof; and/or a stereoisomeror mixture of stereoisomers thereof. In some or any embodiments,provided is a compound of Formula (I) according to Formula (Ic-1):

where R¹, R^(2d), R³, X¹,

and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10; or apharmaceutically acceptable salt or salts thereof; and/or a stereoisomeror mixture of stereoisomers thereof. In some or any embodiments,provided is a compound of Formula (I) according to Formula (Ic-2):

where R¹, R^(2d), R³, X¹, and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof, and/or a stereoisomer or mixture of stereoisomers thereof.

Embodiment 14. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein R^(2d) is hydrogen, halo,C₁-C₆alkyl, C₁₋₆cycloalkyl, C₁-C₃alkoxy, or C₃-C₆-cycloalkyloxy and allother groups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 1-13. In some or anyembodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1),(Ib-1), (Ic-1), or (Ic-2) is that wherein R^(2d) is halo, methyl,methoxy, isopropoxy, or cyclopropyloxy. In some or any embodiments, thecompound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or(Ic-2) is that wherein R^(2d) is C₁-C₆alkoxy, C₁-C₃alkoxy, or methoxy.

Embodiment 15. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein each R^(2b) is hydrogen andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-14.Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1),(Ic-1), or (Ic-2), wherein one R^(2b) is halo, C₁-C₃alkyl, —(CH₂)₀₋₂OH,cyclopropyl, cyano, —CHF₂, —CF₃, C₁-C₄alkoxy, —OCHF₂, —OCF₃, orC₃-C₈cycloalkyloxy and the other R^(2b) are each hydrogen and all othergroups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 1-14.

Embodiment 16: Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein one X¹ is CR³ (optionally inthe meta position with respect to R^(2d)), one X¹ is N, and the other X¹are CR^(2b); or wherein one X¹ is CR³ (optionally in the meta positionwith respect to R^(2d)) and the other X¹ are CR^(2b) (optionally CH);and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-15.

Embodiment 16a. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein one X¹ is CR³ (optionally inthe meta position with respect to R^(2d)), one X¹ is N, and the other X¹are CR²b; and all other groups are as defined in the Summary or in someor any embodiment provided herein, including any one of Embodiments1-15. In some or any embodiments, one X¹ is CR³ (optionally in the metaposition with respect to R^(2d)), one X¹ is N, and the other X¹ are CH.

Embodiment 16b. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein one X¹ is CR³ (optionally inthe meta position with respect to R^(2d)) and the other X¹ are CR^(2b);and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-15. Insome or any embodiments, one X¹ is CR³ (optionally in the meta positionwith respect to R^(2d)) and the other X¹ are CH.

Embodiment 17. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein R³ is —(CH₂)—Y; and all othergroups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 1-16b.

Embodiment 17a. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein R³ is —(CH₂)-L-Y; and allother groups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 1-16b.

Embodiment 17b. Provided is a compound of Formula (Ib) or (Ib-1),wherein R³ is —(CH₂)-L-Y; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-16b.

Embodiment 17c. Provided is a compound of Formula (Ib) or (Ib-1),wherein R³ is —(CH₂)-L-Y; L is —L¹—L²—; and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 1-16b.

Embodiment 17d. Provided is a compound of Formula (Ib) or (Ib-1),wherein R³ is —(CH₂)-L-Y; L is —CH₂—O— or —O—CH₂—; and all other groupsare as defined in the Summary or in some or any embodiment providedherein, including any one of Embodiments 1-16b.

Embodiment 18. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclicheteroaryl (in some embodiments, pyrazolyl) substituted with R^(Y) andoptionally substituted with R^(2e); and all other groups are as definedin the Summary or in some or any embodiment provided herein, includingany one of Embodiments 1-17. Provided is a compound of Formula (I),(Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a6-membered monocyclic aryl substituted with R^(Y) and optionallysubstituted with 1 or 2 R^(2e); and all other groups are as defined inthe Summary or in some or any embodiment provided herein, including anyone of Embodiments 1-17. Provided is a compound of Formula (I), (Ia),(Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 6-memberedmonocyclic heteroaryl substituted with R^(Y) and optionally substitutedwith 1 or 2 R^(2e); and all other groups are as defined in the Summaryor in some or any embodiment provided herein, including any one ofEmbodiments 1-17. Provided is a compound of Formula (I), (Ia), (Ib),(Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 8-memberedbicyclic heteroaryl substituted with R^(Y) and optionally substitutedwith 1 or 2 R^(2e); and all other groups are as defined in the Summaryor in some or any embodiment provided herein, including any one ofEmbodiments 1-17. Provided is a compound of Formula (I), (Ia), (Ib),(Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 9-memberedbicyclic heteroaryl substituted with R^(Y) and optionally substitutedwith 1, 2, or 3 R^(2e); and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-17. Provided is a compound of Formula (I), (Ia), (Ib),(Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 10-memberedbicyclic heteroaryl substituted with R^(Y) and optionally substitutedwith 1, 2, or 3 R^(2e); and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-17. Provided is a compound of Formula (I), (Ia), (Ib),(Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 8- or 9-memberedbicyclic heterocyclic (in some embodiments,

(where R^(Y) is —C(O)R^(3a) where R^(3a) is selected from group a))substituted with R^(Y) and optionally substituted with 1 or 2 R^(2e);and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-17.Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1),(Ic-1), or (Ic-2), wherein Y is a 8- or 9-membered bicyclic heterocyclic(in some embodiments,

(where R^(Y) is —C(O)R^(3a) where R^(3a) is selected from group a))substituted with R^(Y) and optionally substituted with 1 or 2 R^(2e);and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-17.Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1),(Ic-1) or Ic-2) wherein Y is a 8- or 9-membered bicyclic heterocyclic(in some embodiments

(where R^(Y) is —C(O)R^(3a) where R^(3a) is selected from group a))substituted with R^(Y) and optionally substituted with 1 or 2 R^(2e);and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-17.Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1),(Ic-1), or (Ic-2), wherein Y is a 4-9-membered monocyclic or bicyclicheterocycloalkyl substituted with R^(Y) and optionally substituted with1 or 2 R^(2e); and all other groups are as defined in the Summary or insome or any embodiment provided herein, including any one of Embodiments1-17. Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1),(Ib-1), (Ic-1), or (Ic-2), wherein Y is

and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-17.

Embodiment 18a. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclicheteroaryl substituted with R^(Y); Y is a pyrazolyl substituted withR^(Y); Y is a 8- or 9-membered bicyclic heterocyclic substituted withR^(Y); Y is

and R^(Y) is —S(O)₂R^(3a) or —C(O)R^(3a), where R^(3a) is selected fromgroup a); or Y is 4-9-membered monocyclic or bicyclic heterocycloalkylsubstituted with R^(Y); and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-17. Provided is a compound of Formula (I), (Ia), (Ib),(Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-memberedmonocyclic heteroaryl substituted with R^(Y); Y is a pyrazolylsubstituted with R^(Y); Y is a 8- or 9-membered bicyclic heterocyclicsubstituted with R^(Y); Y is

and R^(Y) is —C(O)R^(3a) where R^(3a) is selected from group a); or Y is4-9-membered monocyclic or bicyclic heterocycloalkyl substituted withR^(Y); and all other groups are as defined in the Summary or in some orany embodiment provided herein, including any one of Embodiments 1-17.

Embodiment 18b. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclicheteroaryl substituted with R^(Y); Y is a pyrazolyl substituted withR^(Y); Y is a 8- or 9-membered bicyclic heterocyclic substituted withR^(Y); or Y is

and R^(Y) is —S(O)₂R^(3a) or —C(O)R^(3a), where R^(3a) is selected fromgroup a); and all other groups are as defined in the Summary or in someor any embodiment provided herein, including any one of Embodiments1-17. Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1),(Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclicheteroaryl substituted with R^(Y); Y is a pyrazolyl substituted withR^(Y); Y is a 8- or 9-membered bicyclic heterocyclic substituted withR^(Y); or Y is

and R^(Y) is —C(O)R^(3a), where R^(3a) is selected from group a); andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-17.

Embodiment 18c. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclicheteroaryl substituted with R^(Y); Y is a pyrazolyl substituted withR^(Y); Y is a 8- or 9-membered bicyclic heterocyclic substituted withR^(Y); Y is

and R^(Y) is —S(O)₂R^(3a) or —C(O)R^(3a), where R^(3a) is selected fromgroup a); or Y is 4-9-membered monocyclic or bicyclic heterocycloalkylsubstituted with R^(Y); and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-17. Provided is a compound of Formula (I), (Ia), (Ib),(Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-memberedmonocyclic heteroaryl substituted with R^(Y); Y is a pyrazolylsubstituted with R^(Y); Y is a 8- or 9-membered bicyclic heterocyclicsubstituted with R^(Y); Y is

and R^(Y) is —C(O)R^(3a), where R^(3a) is selected from group a); or Yis 4-9-membered monocyclic or bicyclic heterocycloalkyl substituted withR^(Y); and all other groups are as defined in the Summary or in some orany embodiment provided herein, including any one of Embodiments 1-17.

Embodiment 18d. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclicheteroaryl substituted with R^(Y); Y is a pyrazolyl substituted withR^(Y); Y is a 8- or 9-membered bicyclic heterocyclic substituted withR^(Y); or Y is

and R^(Y) is —S(O)₂R^(3a) or —C(O)R^(3a), where R^(3a) is selected fromgroup a); and all other groups are as defined in the Summary or in someor any embodiment provided herein, including any one of Embodiments1-17. Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1),(Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclicheteroaryl substituted with R^(Y); Y is a pyrazolyl substituted withR^(Y); Y is a 8- or 9-membered bicyclic heterocyclic substituted withR^(Y); or Y is

and R^(Y) is —C(O)R^(3a), where R^(3a) is selected from group a); andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-17.

Embodiment 18e. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclicheteroaryl substituted with R^(Y); Y is a pyrazolyl substituted withR^(Y); Y is a 8- or 9-membered bicyclic heterocyclic substituted withR^(Y); or Y is

and R^(Y) is —S(O)₂R^(3a) or —C(O)R^(3a), where R^(3a) is selected fromgroup a); and all other groups are as defined in the Summary or in someor any embodiment provided herein, including any one of Embodiments1-17. Provided is a compound of Formula (I), (Ia), (Ib), (Ic), (Ia-1),(Ib-1), (Ic-1), or (Ic-2), wherein Y is a 5-membered monocyclicheteroaryl substituted with R^(Y); Y is a pyrazolyl substituted withR^(Y); Y is a 8- or 9-membered bicyclic heterocyclic substituted withR^(Y); or Y is

and R^(Y) is —C(O)R^(3a), where R^(3a) is selected from group a); andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-17.

Embodiment 18f. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein Y is

and R^(Y) is —S(O)₂R^(3a) or —C(O)R^(3a), where R^(3a) is selected fromgroup a); HET1 is a 5- to 7-membered heterocycloalkyl; and all othergroups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 1-17. Provided is acompound of Formula (I), (Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or(Ic-2), wherein Y is

and R^(Y) is —S(O)₂R^(3a) or —C(O)R^(3a), where R^(3a) is selected fromgroup a); HET1 is a 5- to 7-membered heterocycloalkyl containing 1 or 2nitrogen atoms in the ring; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-17.

Embodiment 19. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein R^(3b) and R^(3b1) are eachhydrogen; and all other groups are as defined in the Summary or in someor any embodiment provided herein, including any one of Embodiments1-18a.

Embodiment 20. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein R^(Y) is—(CH₂)₀₋₃NHC(O)R^(3a), —(CH₂)₀₋₂NHS(O)₂R^(3a), —C(O)R^(3a),—S(O)₂R^(3a), —(CH₂)₀₋₃NR^(3b)(C₁-C₆alkylene)NR^(3b1)C(O)R^(3a),—(CH₂)₀₋₃NR^(3b)(C₁-C₆alkylene)NR^(3b1)S(O)₂R^(3a),—(CH₂)₀₋₃NR^(3b)C(O)(C₁-C₆alkylene)NR^(3b1)C(O)R^(3a),—(CH₂)₀₋₃NR^(3b)C(O)(C₁-C₆alkylene)NR^(3b1)S(O)₂R^(3a), orC₃-C₈heterocycloalkyl substituted with —C(O)R^(3a); where R^(3a) isselected from group a); and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-19.

Embodiment 21. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein R^(3a) is —CH₂(halo);—(CH₂)₁₋₂CN; —CH₂OCH(CF₃)₂; —CH₂O(trifluorophenyl);—CH₂O(tetrafluorophenyl); —CH₂O(isoxazolyl, optionally substituted with1-3 substituents each independently selected from halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkoxy, cyano, C₃₋₈cycloalkyl or C₃₋₈heterocycloalkyl);—CH₂O(pyrimidinyl, optionally substituted with 1-3 substituents eachindependently selected from halo, C₁₋₆alkyl, C₂-6alkenyl, C₁₋₆alkoxy,cyano, C₃₋₈cycloalkyl or C₃₋₈heterocycloalkyl); —CH₂O(pyridyl,optionally substituted with 1-3 substituents each independently selectedfrom halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₁₋₆alkoxy, cyano, C₃₋₈cycloalkyl orC₃₋₈heterocycloalkyl); C₂-C₆alkenyl; C₂-C₄alkenyl substituted with cyano(in some embodiments, —C(CN)(═CH₂)); C₂-C₄alkenyl substituted with halo(in some embodiments, C₂-C₄alkenyl substituted with fluoro);—CH═CH—CH₂—NR^(3c)R^(3d); —CH═CH—CH₂—O—C₁-C₆alkyl; trifluorophenyl;tetrafluorophenyl; C₂-C₆alkynyl; —CH≡CH—CH₂—NR^(3c)R^(3d); or—CH≡CH—CH₂—O—C₁-C₆alkyl; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-20.

Embodiment 21a. Provided is a compound of Formula (Ib) or (Ib-1),wherein R^(3a) is C₁-C₆alkyl substituted with 1 or 2 halo which areindependently selected; C₁-C₆alkyl substituted with cyano; C₂-C₆alkenylsubstituted with cyano (in some embodiments, —C(CN)(═CH₂)); C₂-C₆alkenylsubstituted with halo (in some embodiments, C₂-C₄alkenyl substitutedwith fluoro); —CH═CH—CH₂—NR^(3c)R^(3d); —CH═CH—CH₂—O—C₁-C₆alkyl;C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;—CH≡CH—CH₂—NR^(3c)R^(3d); CH≡CH—CH₂—OH; —CH≡CH—CH₂—O—C₁-C₆alkyl;spirocycloalkyl substituted with cyano; pentafluorophenyl;tetraflurophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl;and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-20.

Embodiment 22. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein R^(Y) is

and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-19.

Embodiment 22a. Provided is a compound of Formula (I) (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein R^(Y) is

and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-19.

Embodiment 23. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein one R^(2b) is fluoro,C₁-C₃alkyl, —(CH₂)₀₋₂OH, cyclopropyl, —CHF₂, —CF₃, C₁-C₄alkoxy, —OCHF₂,or —OCF₃ and the other are hydrogen; and all other groups are as definedin the Summary or in some or any embodiment provided herein, includingany one of Embodiments 1-22. Provided is a compound of Formula (I),(Ia), (Ib), (Ic), (Ia-1), (Ib-1), (Ic-1), or (Ic-2), wherein each R^(2e)is hydrogen or —OH; and all other groups are as defined in the Summaryor in some or any embodiment provided herein, including any one ofEmbodiments 1-22.

Embodiment 24. Provided is a compound of Formula (I) according toFormula (Id):

where R¹, X^(2a), X², and all other groups are as defined in the Summaryor in some or any embodiment provided herein, including any one ofEmbodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof; and/or a stereoisomer or mixture of stereoisomers thereof. Insome or any embodiments, provided is a compound of Formula (I) accordingto Formula (Id-1):

where R¹, X^(2a), R⁴, and X² and other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof, and/or a stereoisomer or mixture of stereoisomers thereof.

Embodiment 25. Provided is a compound of Formula (I), (Id), or (Id-1),wherein each R^(2b) is hydrogen; and all other groups are as defined inthe Summary or in some or any embodiment provided herein, including anyone of Embodiments 1-10 and 24. Provided is a compound of Formula (I),(Id), or (Id-1), wherein one R^(2b) is halo, C₁-C₃alkyl, —(CH₂)₀₋₂OH,cyclopropyl, cyano, —CHF₂, —CF₃, C₁-C₄alkoxy, —OCHF₂, —OCF₃, orC₃-C₈cycloalkyloxy and the other R^(2b) are each hydrogen and all othergroups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 1-9 and 24.

Embodiment 26: In some or any embodiments, one X¹ is CR³ (optionally inthe meta position with respect to R^(2d)), one X¹ is N, and the other X¹are CR^(2b); or wherein one X¹ is CR³ (optionally in the meta positionwith respect to R^(2d)) and the other X¹ are CR^(2b)(optionally CH) andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10, 24,and 25. In some or any embodiments, one X¹ is CR³ (optionally in themeta position with respect to R^(2d)), one X¹ is N, and the other X¹ areCR^(2b) and all other groups are as defined in the Summary or in some orany embodiment provided herein, including any one of Embodiments 1-10,24, and 25. In some or any embodiments, one X¹ is CR³ (optionally in themeta position with respect to R^(2d)), one X¹ is CR³ (optionally in themeta position with respect to R^(2d)) and the other X¹ are CR^(2b)(optionally CH) and all other groups are as defined in the Summary or insome or any embodiment provided herein, including any one of Embodiments1-10, 24, and 25.

Embodiment 26. Provided is a compound of Formula (I), (Id), or (Id-1),wherein one X² is CR⁴ and the other X² are CR²b; and all other groupsare as defined in the Summary or in some or any embodiment providedherein, including any one of Embodiments 1-10, 24, and 25. In some orany embodiments, one X² is CR⁴ and the other X² are CH.

Embodiment 27. Provided is a compound of Formula (I), (Id), or (Id-1),wherein X^(2a) is O; and all other groups are as defined in the Summaryor in some or any embodiment provided herein, including any one ofEmbodiments 1-10, and 24-26. Provided is a compound of Formula (I),(Id), or (Id-1), wherein X^(2a) is S; and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 1-10, and 24-26.

Embodiment 28. Provided is a compound of Formula (I), (Id), or (Id-1),wherein R^(4b) and R^(4b1) are each hydrogen; and all other groups areas defined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 1-10, and 24-27.

Embodiment 29. Provided is a compound of Formula (I), (Id), or (Id-1),wherein R⁴ is —(CH₂)₀₋₃NR^(4b)C(O)R^(4a), —(CH₂)₀₋₂NR^(4b)S(O)₂R^(4a),—C(O)R^(4a), —C(O)NR^(4b)R^(4a),—NR^(4b)(C₁-C₆alkylene)NR^(4b1)C(O)R^(4a),—(CH₂)₀₋₃NR^(4b)C(O)(C₁-C₆alkylene)NR^(4b1)C(O)R^(4a),—C(O)NR^(4b)(C₁-C₆alkylene)NR^(4b1)C(O)R^(4a), —C(O)—HET1—C(O)R^(4a),—C(O)—HET1—NR^(4b)C(O)R^(4a), —(CH₂)₀₋₃NR^(4b)C(O)-HET1—C(O)R^(4a),C₃-C₈heterocycloalkyl substituted with —C(O)R^(4a) (preferably where theC₃-C₈heterocycloalkyl is attached to ring (d) through a carbon in theC₃-C₈heterocycloalkyl ring); or —(CH₂)₀₋₂HET2—C(O)R^(4a); where R^(4a)is selected from group a); and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10, and 24-28.

Embodiment 29a. Provided is a compound of Formula (I), (Id), or (Id-1),wherein R⁴ is

-   -   —(CH₂)₀₋₂NHC(O)R^(4a);    -   —NH(C₂-C₄-alkylene)NHC(O)R^(4a);    -   C₃-C₈heterocycloalkyl substituted with —C(O)R^(4a) on a nitrogen        ring atom in the C₃-C₈heterocycloalkyl (preferably where the        C₃-C₈heterocycloalkyl is attached to ring (d) through a carbon        in the C₃-C₈heterocycloalkyl ring);    -   —C(O)—HET1—C(O)R^(4a) where —C(O)R^(4a) is attached to a        nitrogen ring atom in HET1; —C(O)—HET1-NHC(O)R^(4a) where —C(O)—        is attached to a nitrogen ring atom in HET1;    -   —C(O)NH(C₁-C₆alkylene)NHC(O)R^(4a);    -   —(CH₂)₀₋₂HET2—C(O)R^(4a) where HET2 is a 5-membered monocyclic        heteroaryl or is a 8- or 9-membered bicyclic heterocyclic and        where the —C(O)R^(4a) is to attached to HET2 through a nitrogen        ring atom in HET2;    -   —(CH₂)₀₋₃NHC(O)(C₁-C₆alkylene)NHC(O)R^(4a); or    -   —(CH₂)₀₋₃NHC(O)-HET1—C(O)R^(4a);        where R^(4a) is selected from group a); and all other groups are        as defined in the Summary or in some or any embodiment provided        herein, including any one of Embodiments 1-10, and 24-28.

Embodiment 30. Provided is a compound of Formula (I), (Id), or (Id-1),wherein R^(4a) is —CH₂(halo); —(CH₂)₁-2CN; C₂-C₆alkenyl; C₂-C₄alkenylsubstituted with cyano; C₂-C₄alkenyl substituted with halo;—CH═CH—CH₂—NR^(4c)R^(4d); —CH═CH—CH₂—O—C₁-C₆alkyl; C₂-C₆alkynyl;—CH≡CH—CH₂—NR^(4c)R^(4d); or —CH≡CH—CH₂—O—C₁-C₆alkyl; and all othergroups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 1-10, and 24-29a.

Embodiment 30a. Provided is a compound of Formula (I), (Id), or (Id-1),wherein R^(4a) is C₁-C₆alkyl substituted with 1 or 2 halo which areindependently selected; C₁-C₆alkyl substituted with cyano; C₂-C₆alkenylsubstituted with cyano (in some embodiments, —C(CN)(═CH₂)); C₂-C₆alkenylsubstituted with halo (in some embodiments, C₂-C₄alkenyl substitutedwith fluoro); —CH═CH—CH₂—NR^(4c)R^(4d); —CH═CH—CH₂—O—C₁-C₆alkyl;C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; C₂-C₆alkynyl;—CH≡CH—CH₂—NR^(4c)R^(4d); CH—CH—CH₂—OH; —CH≡CH—CH₂—O—C₁-C₆alkyl;spirocycloalkyl substituted with cyano; pentafluorophenyl;tetraflurophenyl; trifluorophenyl; difluorophenyl; or monofluorophenyl;and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10, and24-29a.

Embodiment 31. Provided is a compound of Formula (I), (Id), or (Id-1),wherein HET1—C(O)R^(4a) is

HET1-NHC(O)R^(4a) is

and HET2-C(O)R^(4a) is

where R^(4a) is selected from group a); and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 1-10, and 24-30.

Embodiment 32. Provided is a compound of Formula (I), (Id), or (Id-1),wherein R⁴ is

and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10, and24-28.

Embodiment 32a. Provided is a compound of Formula (I), (Id), or (Id-1),wherein R⁴ is

and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10, and24-28.

Embodiment 33. Provided is a compound of Formula (I) according toFormula (Ie):

where R¹, R^(2b), R⁵, and all other groups are as defined in the Summaryor in some or any embodiment provided herein, including any one ofEmbodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof; and/or a stereoisomer or mixture of stereoisomers thereof. Insome or any embodiments, provided is a compound of Formula (I) accordingto Formula (Ie-1):

where R¹, R^(2b), R⁵, and other groups are as defined in the Summary orin some or any embodiment provided herein, including any one ofEmbodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof, and/or a stereoisomer or mixture of stereoisomers thereof.

Embodiment 34. Provided is a compound of Formula (I) according toFormula (If):

where R¹, R^(2b), R⁵, and all other groups are as defined in the Summaryor in some or any embodiment provided herein, including any one ofEmbodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof; and/or a stereoisomer or mixture of stereoisomers thereof. Insome or any embodiments, provided is a compound of Formula (I) accordingto Formula (If-1).

where R¹, R^(2b), R⁵, and all other groups are as defined in the Summaryor in some or any embodiment provided herein, including any one ofEmbodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof, and/or a stereoisomer or mixture of stereoisomers thereof.

Embodiment 35. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein each R^(2b) is independently hydrogen orC₁-C₃alkyl; and all other groups are as defined in the Summary or insome or any embodiment provided herein, including any one of Embodiments1-10 and 34. In some or any embodiments, each R^(2b) is independentlyhydrogen or methyl.

Embodiment 36. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein R⁵ is pyridinyl, pyrazolyl, or imidazolyl;each of which is substituted with Z and optionally substituted withR^(2e); and all other groups are as defined in the Summary or in some orany embodiment provided herein, including any one of Embodiments 1-10,34, and 35.

Embodiment 36a. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein R⁵ is —C(O)N(R^(5b))Z where R^(5b) isselected from group b); and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10, 34, and 35. In a subembodiment of Embodiment 36a,provided is a compound of Formula (I), (Ie), (If), (Ie-1), or (If-1),wherein R⁵ is —C(O)NHZ; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10, 34, and 35.

Embodiment 36b. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein R⁵ is heterocycloalkyl (in some embodiments,pyrrolidinyl) substituted with Z and optionally substituted with R^(2e);and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10, 34,and 35.

Embodiment 36c. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein R⁵ is —(CH₂)₀₋₂O-HET1-Z; and all other groupsare as defined in the Summary or in some or any embodiment providedherein, including any one of Embodiments 1-10, 34, and 35.

Embodiment 36d. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein R⁵ is —(CH₂)₀₋₂O—Z; and all other groups areas defined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 1-10, 34, and 35.

Embodiment 37. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein R^(5a) is —CH₂(halo); —(CH₂)₁-2CN;C₂-C₆alkenyl; C₂-C₄alkenyl substituted with cyano; C₂-C₄alkenylsubstituted with halo; —CH═CH—CH₂—NR^(5c)R^(5d);—CH═CH—CH₂—O—C₁-C₆alkyl; C₂-C₆alkynyl; —CH≡CH—CH₂—NR^(5c)R^(5d);CH≡CH—CH₂—OH; —CH≡CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted withcyano; pentafluorophenyl; tetraflurophenyl; trifluorophenyl;difluorophenyl; or monofluorophenyl; and all other groups are as definedin the Summary or in some or any embodiment provided herein, includingany one of Embodiments 1-10 and 34-36.

Embodiment 38. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein each R^(5b) and R^(5b1) are each hydrogen;and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10, and34-37.

Embodiment 39. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein Z is —(CH₂)₀₋₃NHC(O)R^(5a),—(CH₂)₀₋₂NHS(O)₂R^(5a), —C(O)R^(5a), —S(O)₂R^(5a),—(CH₂)₀₋₃—C(O)NHR^(5a), —(CH₂)₀₋₃NH(C₁-C₆alkylene)NHC(O)R^(5a),C₃-C₈heterocycloalkyl substituted with —NHC(O)R^(5a),C₃-C₈heterocycloalkyl substituted with —S(O)₂R^(5a), orC₃-C₈heterocycloalkyl substituted with —C(O)R^(5a); where R^(5a) isselected from group a); and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10 and 34-38.

Embodiment 40. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein wherein Z is

and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10, and34-36.

Embodiment 40. Provided is a compound of Formula (I), (Ie), (If),(Ie-1), or (If-1), wherein wherein Z is

and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10, and34-36.

Embodiment 41. Provided is a compound of Formula (I) according toFormula (Ig):

where R¹, Q¹, Q², Q³, R⁶, R⁷, and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof; and/or a stereoisomer or mixture of stereoisomers thereof. Insome or any embodiments, provided is a compound of Formula (I) accordingto Formula (Ig-1):

where R¹, Q¹, Q², Q³, R⁶, R⁷, and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10; or a pharmaceutically acceptable salt or saltsthereof; and/or a stereoisomer or mixture of stereoisomers thereof.

Embodiment 42. Provided is a compound of Formula (I), (Ig), or (Ig-1),wherein Q¹ is CR^(Q1), Q² is O, and Q³ is N; and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 1-10 and 41. Provided is a compound ofFormula (I), (Ig), or (Ig-1), wherein Q¹ is S, Q² is N, and Q³ is N; andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 1-10 and41. Provided is a compound of Formula (I), (Ig), or (Ig-1), wherein Q¹is N, Q² is N, and Q³ is O; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10 and 41. Provided is a compound of Formula (I), (Ig),or (Ig-1), wherein Q¹ is O, Q² is N, and Q³ is N; and all other groupsare as defined in the Summary or in some or any embodiment providedherein, including any one of Embodiments 1-10 and 41. Provided is acompound of Formula (I), (Ig), or (Ig-1), wherein Q¹ is CR^(Q1)(optionally wherein R^(Q1) is hydrogen), Q² is N, and Q³ is O; and allother groups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 1-10 and 41. In someor any embodiments, R^(Q1) is hydrogen, C(O)CH₃, or C₁. In some or anyembodiments, R^(Q1) is hydrogen.

Embodiment 43. Provided is a compound of Formula (I), (Ig), or (Ig-1),wherein R⁶ is a pyrazolyl substituted with Q and optionally substitutedwith R^(2e); or R⁶ is —(CH₂)₀₋₃NHC(O)R^(6a); where R^(6a) is selectedfrom group a); and all other groups are as defined in the Summary or insome or any embodiment provided herein, including any one of Embodiments1-10 and 42.

Embodiment 44. Provided is a compound of Formula (I), (Ig), or (Ig-1),wherein R^(6a) is —CH₂(halo); —(CH₂)₁-2CN; C₂-C₆alkenyl; C₂-C₄alkenylsubstituted with cyano; C₂-C₄alkenyl substituted with halo;—CH═CH—CH₂—NR^(3c)R^(3d); —CH═CH—CH₂—O—C₁-C₆alkyl; tetrafluorophenyl;trifluorophenyl; C₂-C₆alkynyl; —CH≡CH—CH₂—NR^(3c)R^(3d); or—CH≡CH—CH₂—O—C₁-C₆alkyl; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10 and 43.

Embodiment 44a. Provided is a compound of Formula (I), (Ig), or (Ig-1),wherein R^(6a) is C₁-C₆alkyl substituted with 1 or 2 halo which areindependently selected; C₁-C₆alkyl substituted with cyano; C₂-C₆alkenylsubstituted with cyano (in some embodiments, —C(CN)(═CH₂)); C₂-C₆alkenylsubstituted with halo (in some embodiments, C₂-C₄alkenyl substitutedwith fluoro); —CH═CH—CH₂—NR^(6c)R^(6d); —CH═CH—CH₂—O—C₁-C₆alkyl;C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl; tetrafluorophenyl;trifluorophenyl; C₂-C₆alkynyl; —CH≡CH—CH₂—NR^(6c)R^(6d); CH≡CH—CH₂—OH;—CH≡CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted with cyano; and allother groups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 1-10 and 43.

Embodiment 45. Provided is a compound of Formula (I), (Ig), or (Ig-1),wherein R^(6b) is hydrogen; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 1-10 and 42.

Embodiment 46. Provided is a compound of Formula (I), (Ig), or (Ig-1),wherein one R⁷ is C₁-C₆alkyl, C₁-C₆alkoxy, or C₃-C₈cycloalkyl; and allother groups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 1-10 and 45.

Embodiment 47. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (le), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1),(If-1), or (Ig-1), wherein R^(3c), R^(3d), R^(4a), R^(4d), R^(5c),R^(5d), R^(6c), and R^(6d) are each independently hydrogen orC₁-C₃alkyl; or where each pair of R^(3c) and R^(3d), R^(4c) and R^(4d),R^(5c) and R^(5d), and R^(6c) and R^(6d), together with the nitrogen towhich they are attached, form a pyrrolidinyl or piperidinyl; and allother groups are as defined in the Summary or in some or any embodimentprovided herein, including any one of preceding embodiments.

Embodiment 47a. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (le), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1),(If-1), or (Ig-1), wherein R^(3a), R^(4a), R^(5a), and R^(6a) are—CH₂(halo); —(CH₂)₁₋₂CN; C₂-C₆alkenyl; C₂-C₄alkenyl substituted withcyano; C₂-C₄alkenyl substituted with halo; —CH═CH—CH₂—NR^(3c)R^(3d);—CH═CH—CH₂—O—C₁-C₆alkyl; tetrafluorophenyl; trifluorophenyl;C₂-C₆alkynyl; —CH≡CH—CH₂—NR^(3c)R^(3d); or —CH≡CH—CH₂—O—C₁-C₆alkyl; andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of preceding embodiments.

Embodiment 47b. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (le), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1),(If-1), or (Ig-1), wherein R^(Y) is

R⁴ is

and Z is

and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of preceding embodiments.

Embodiment 47c. Provided is a compound of Formula (I), (Ia), (Ib), (Ic),(Id), (le), (If), (Ig), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1),(If-1), or (Ig-1), wherein R^(Y) is

-   -   R⁴ is

-   -    and    -   Z is

-   -    and all other groups are as defined in the Summary or in some        or any embodiment provided herein, including any one of        preceding embodiments.

Embodiment 48: Provided is a compound where the 8- or 9-memberedbicyclic heterocyclic (optionally substituted as provided herein) is a5-membered heteroaryl group, preferably a pyrazolyl, fused to anonaromatic cyclic group, preferably forming an 8-membered bicyclicheterocyclic, which is optionally substituted as provided herein. In anembodiment of Embodiment 48, provided is a compound where the 8- or9-membered bicyclic heterocyclic (optionally substituted as providedherein) is a 5-membered heteroaryl group, preferably a pyrazolyl, fusedto a nonaromatic cyclic group, preferably forming an 8-membered bicyclicheterocyclic group, which is optionally substituted as provided herein;and where the rest of the molecule is attached to the 5-memberedheteroaryl group fused to the nonaromatic cyclic group through the5-membered heteroaryl portion. In an embodiment of Embodiment 48,provided is a compound where the nonaromatic portion of the 8- or9-membered bicyclic heterocyclic (optionally substituted as providedherein) comprises a heteroatom in the ring, preferably nitrogen.

Embodiment 49: Provided is a pharmaceutical composition comprising aCompound of any one of Embodiments 1-48 or a stereoisomer, a mixture ofstereoisomers, and/or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier.

Embodiment 50: Provided is a method of treating a condition, disease, ordisorder by inhibiting MYST family of lysine acetyl transferases,including KAT6A and KAT6B, comprising administering to a patient in needthereof a therapeutically effective amount of the Compound of any one ofEmbodiments 1-48 or a stereoisomer, a mixture of stereoisomers, and/or apharmaceutically acceptable salt thereof or a therapeutically effectiveamount of the composition of Embodiment 4.

Embodiment 51: Provided is the method of embodiment 50 where thecondition, disease, or disorder is a hyperproliferative disease, such ascancer. In some or any embodiments, the cancer is a particular typeselected from: lymphoma, melanoma, carcinoma (e.g. adenocarcinoma,hepatocellular carcinoma, medullary carcinoma, papillary carcinoma,squamous cell carcinoma), astrocytoma, glioma, medulloblastoma, myeloma,meningioma, neuroblastoma, and sarcoma (e.g. angiosarcoma,chrondrosarcoma, osteosarcoma). In some or any embodiments, the cancermay be a MYST overexpressing cancer; the cancer may over-express MYSTprotein relative to non-cancerous tissue; the cancer may overproduceMYST mRNA relative to non-cancerous tissue; the cancer may be a MYSToverexpressing cancer where the overexpressed MYST protein or MYST mRNAmay be any one of KATs of the MYST family, e.g. KAT6A. In some or anyembodiments, the cancer is selected from one or more of the followingleukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia(AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia(CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lungcancer, melanoma, breast cancer, breast ductal carcinoma, colon andrectal cancer, colon cancer, squamous cell carcinoma, gastric cancer,adrenocortical cancer, anal cancer, bladder cancer, blood cancer, bonecancer, brain tumor, cancer of the female genital system, cancer of themale genital system (including testicular cancer and penile cancer),central nervous system lymphoma, cervical cancer, childhoodrhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrialsarcoma, esophageal cancer, eye cancer, gallbladder cancer,gastrointestinal tract cancer, hairy cell leukemia, head and neckcancer, hepatocellular cancer, hypopharyngeal cancer, Kaposi's sarcoma,kidney cancer, laryngeal cancer, liver cancer, malignant fibroushistiocytoma, malignant thymoma, mesothelioma, multiple myeloma,myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,nervous system cancer, neuroblastoma, oral cavity cancer, oropharyngealcancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroidcancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm,primary CNS lymphoma, rectal cancer, respiratory system, retinoblastoma,salivary gland cancer, skin cancer, small intestine cancer, soft tissuesarcoma, stomach cancer, testicular cancer, thyroid cancer, urinarysystem cancer, uterine cancer, uterine sarcoma, vaginal cancer,endocrine, neoplasms of the central nervous system (CNS), primary CNSlymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitaryadenoma, vascular system, Waldenstrom's macroglobulinemia and/or Wilms'tumor. In some or any embodiments, the cancer is breast cancer,including ER positive breast cancer, non-small cell lung cancer,prostate cancer, pancreatic cancer, ovarian cancer, or blood cancer(including a leukemia or lymphoma).

Embodiment B: In one embodiment is a compound of Formula (I) where

-   -   R¹ is unsubstituted C₃₋₈cycloalkylalkyl, preferably        cyclohexylmethyl, or phenyl where the phenyl is optionally        substituted with one or two groups independently selected from        halo, preferably fluoro, and C₁₋₃alkoxy, preferably methoxy;    -   R² is ring (a) or ring (b); where one X¹ is C(CH₂R^(2c)), and        the other two X¹ are each CH; preferably, the C(CH₂R^(2c)) is in        the meta-position with respect to R^(2d);    -   R^(2b) is hydrogen or C₁-C₆alkyl, preferably hydrogen or methyl;    -   R^(2c) is a 5-membered heteroaryl, preferably pyrazol-1-yl,        optionally substituted with cyano or —CH₂NHC(O)CH₃; or R^(2c) is        2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl optionally        substituted with C₁₋₆alkylcarbonyl; or R^(2c) is a 6-membered        heteroaryl, preferably pyridin-2-yl;    -   R^(2d) is C₁₋₃alkoxy; or    -   a pharmaceutically acceptable salt or salts thereof; and/or a        stereoisomer or mixture of stereoisomers thereof.

Embodiment 52. Provided is a compound of Formula (I) according toFormula (Ih):

where R¹, R^(2b), R^(2d), and X¹ and all other groups are as defined inthe Summary or in some or any embodiment provided herein; or apharmaceutically acceptable salt or salts thereof; and/or a stereoisomeror mixture of stereoisomers thereof. In some or any embodiments ofEmbodiment 52, R^(2b) is hydrogen or methyl.

Embodiment 53. Provided is a compound of Formula (I) according toFormula (Ii):

where R¹, R^(2d), and X¹ and all other groups are as defined in theSummary or in some or any embodiment provided herein; or apharmaceutically acceptable salt or salts thereof; and/or a stereoisomeror mixture of stereoisomers thereof.

Embodiment 54. Provided is a compound of Formula (I) according toFormula (Ij):

where R¹, R^(2d), X¹, and X² and all other groups are as defined in theSummary or in some or any embodiment provided herein; or apharmaceutically acceptable salt or salts thereof; and/or a stereoisomeror mixture of stereoisomers thereof.

Embodiment 55: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein R¹ is C₃-C₈-cycloalkylalkyl where theC₃-C₈-cycloalkylalkyl is optionally substituted with 1, 2, or 3 R^(1a),or phenyl optionally substituted with 1, 2, or 3 R^(1b); and all othergroups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 52-54.

Embodiment 56: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein R¹ is C₃-C₈-cycloalkylalkyl where theC₃-C₈-cycloalkylalkyl is optionally substituted with 1, 2, or 3 R^(1a);and all other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 52-54.

Embodiment 57: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein each R^(1a) is independently H; and all othergroups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 52-56.

Embodiment 58: Provided is a compound according to Formula (I), (Ih),(Ii), or (IIc), wherein R¹ is phenyl optionally substituted with 1, 2,or 3 R^(1b); and all other groups are as defined in the Summary or insome or any embodiment provided herein, including any one of Embodiments52-55.

Embodiment 59: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein R¹ is naphthyl optionally substituted with 1, 2,or 3 R^(1b); and all other groups are as defined in the Summary or insome or any embodiment provided herein, including any one of Embodiments52-54.

Embodiment 60: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein R¹ is 5- or 6-membered monocyclic heteroaryloptionally substituted with 1, 2, or 3 R^(1b); and all other groups areas defined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 52-54.

Embodiment 60a: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein R¹ is 8-10-membered bicyclic heteroaryl; and allother groups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 52-54.

Embodiment 61: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein each R^(1b) is independently selected from H,halo, and C₁-C₆alkoxy; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 52-55 and 58-60. In a subembodiment of embodiment 61,provided is compound of Formula (I), (Ih), (Ii), or (Ij) wherein eachR^(1b) is independently selected from H, halo, and C₁-C₃alkoxy. In asubembodiment of embodiment 61, provided is compound of Formula (I),(Ih), (Ii), or (Ij) wherein each R^(1b) is independently selected fromH, fluoro, and methoxy. In a subembodiment of embodiment 61 andsubembodiments thereof, provided is compound of Formula (I), (Ih), (Ii),or (Ij) wherein one or two R^(1b) are present. In a subembodiment ofembodiment 61 and subembodiments thereof, provided is compound ofFormula (I), (Ih), (Ii), or (Ij) wherein one R^(1b) are present. In asubembodiment of embodiment 61 and subembodiments thereof, provided iscompound of Formula (I), (Ih), (Ii), or (Ij) wherein two R^(1b) arepresent.

Embodiment 62: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein R^(2d) is halo, C₁-C₃alkyl, C₁-C₃alkoxy, orC₃-cycloalkyloxy; and all other groups are as defined in the Summary orin some or any embodiment provided herein, including any one ofEmbodiments 52-61. In a subembodiment of embodiment 62, provided iscompound of Formula (I), (Ih), (Ii), or (Ij) wherein R^(2d) isC₁-C₆alkoxy, preferably C₁-C₃alkoxy, preferably methoxy. In asubembodiment of embodiment 62, provided is compound of Formula (I),(Ih), (Ii), or (Ij) wherein R^(2d) is methoxy, isopropoxy, orcyclopropyloxy.

Embodiment 63: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein each R^(2e) is independently hydrogen, fluoro,C₁-C₃alkyl, cyclopropyl, —CHF₂, —CF₃, C₁-C₄alkoxy, —OCHF₂, or —OCF₃; andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 52-61. In asubembodiment of embodiment 63, provided is compound of Formula (I),(Ih), (Ii), or (Ij) wherein each R^(2e) is hydrogen.

Embodiment 64: Provided is a compound according to Formula (I) or (Ih),wherein

-   -   R^(2c) is a 5-membered monocyclic heteroaryl optionally        substituted with 1 or 2 R^(2c1); R^(2c) is a 8- or 9-membered        bicyclic heterocyclic optionally substituted with 1 or 2        R^(2c1); R^(2c) is a 6-membered monocyclic heteroaryl optionally        substituted with 1, 2, or 3 R^(2c1); and    -   each R^(2c1) is independently H, halo, C₁-C₆alkyl,        C₁-C₆alkylcarbonyl, —CN, C₁-C₆alkoxy, C₃-C₈cycloalkyloxy,        —(CH₂)₀₋₁NH₂, —(CH₂)₀₋₁NHC(O)R^(2f),        —(CH₂)₀₋₁NHC(O)OR^(2f)—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, 5- or        6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclic        heteroaryl; wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl, or        C₃-C₆cycloalkylC₁-C₃alkyl;        and all other groups are as defined in the Summary or in some or        any embodiment provided herein, including any one of Embodiments        55-63. In a subembodiment of Embodiment 64, provided is a        compound where R^(2c) is a 5-membered monocyclic heteroaryl        optionally substituted with 1 or 2 R^(2c1); R^(2c) is a        8-membered bicyclic heterocyclic optionally substituted with 1        or 2 R^(2c1); or R^(2c) is a 6-membered monocyclic heteroaryl        optionally substituted with 1, 2, or 3 R^(2c1).

Embodiment 64a: In an embodiment of Embodiment 64, provided is acompound where each R^(2c1) is hydrogen (i.e. R^(2c) is notsubstituted); and all other groups are as defined in the Summary or insome or any embodiment provided herein, including any one of Embodiments55-63. In a subembodiment of Embodiment 64, provided is a compound whereone R^(2c1) is hydrogen and the other R^(2c1) is selected fromC₁-C₆alkylcarbonyl, —CN, —(CH₂)₀₋₁NH₂, and —(CH₂)₀₋₁NHC(O)R^(2f),—(CH₂)₀₋₁NHC(O)OR²f; wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl, orC₃-C₆cycloalkylC₁-C₃alkyl; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 55-63. In a subembodiment of Embodiment 64, provided is acompound where one R^(2c1) is hydrogen and the other R^(2c1) is —CN; andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 55-63.

Embodiment 64b: In a subembodiment of Embodiment 64 or 64a, provided isa compound where R^(2c) is pyrazolyl, pyridinyl, or2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is optionallysubstituted with 1 or 2 R^(2c1). In a subembodiment of Embodiment 64 or64a, provided is a compound where R^(2c) is a 5-membered monocyclicheteroaryl optionally substituted with 1 or 2 R^(2c1). In asubembodiment of Embodiment 64 or 64a, provided is a compound whereR^(2c) is a 8-membered bicyclic heterocyclic optionally substituted with1 or 2 R^(2c1). In a subembodiment of Embodiment 64 or 64a, provided isa compound where R^(2c) is a 6-membered monocyclic heteroaryl optionallysubstituted with 1, 2, or 3 R^(2c1).

Embodiment 64c: In an embodiment of Embodiment 64, provided is acompound where R^(2c) is pyrazolyl, preferably pyrazol-2-yl, and isunsubstituted (i.e. both R^(2c1) are hydrogen) or is substituted withone R^(2c1) which is preferably cyano (i.e. the other R^(2c1) ishydrogen); and all other groups are as defined in the Summary or in someor any embodiment provided herein, including any one of Embodiments55-63. In an embodiment of Embodiment 64, provided is a compound whereR^(2c) is pyridinyl, preferably pyridin-2-yl, and is unsubstituted (i.e.both R^(2c1) are hydrogen) or is substituted with one R^(2c1) which iscyano (i.e. the other R^(2c1) is hydrogen); and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 55-63. In an embodiment of Embodiment64, provided is a compound where R^(2c) is2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, preferably2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, and is unsubstituted (i.e.both R^(2c1) are hydrogen) or is substituted with one R^(2c1) (i.e. theother R^(2c1) is hydrogen) where the one R^(2c1) is alkylcarbonyl,preferably, methylcarbonyl or ethylcarbonyl; and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 55-63.

Embodiment 64d: In an embodiment of Embodiment 64 or 64a, provided is acompound where R^(2c) is a 8- or 9-membered bicyclic heterocyclicoptionally substituted with 1 or 2 R^(2c1); and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 55-63.

Embodiment 64d-1: In a sub-embodiment of Embodiment 64d, provided is acompound where the 8- or 9-membered bicyclic heterocyclic (optionallysubstituted with 1 or 2 R^(2c1)) is a 5-membered heteroaryl group,preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferablyforming an 8-membered bicyclic heterocyclic, which is optionallysubstituted with 1 or 2 R^(2c1).

Embodiment 64d-2: In a sub-embodiment of Embodiment 64d, provided is acompound where the 8- or 9-membered bicyclic heterocyclic (optionallysubstituted with 1 or 2 R^(2c1)) is a 5-membered heteroaryl group,preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferablyforming an 8-membered bicyclic heterocyclic group, which is optionallysubstituted with 1 or 2 R^(2c1); and where the rest of the molecule isattached to the 5-membered heteroaryl group fused to the nonaromaticcyclic group through the 5-membered heteroaryl portion.

Embodiment 64d-3: In a sub-embodiment of any one of Embodiments 64d,64d-1, and 64d-2, provided is a compound where the nonaromatic portionof the 8- or 9-membered bicyclic heterocyclic (optionally substitutedwith 1 or 2 R^(2c1)) comprises a heteroatom in the ring, preferablynitrogen.

Embodiment 64d-4: In a sub-embodiment of any one of Embodiments 64d,64d-1, 64d-2, and 64d-3, provided is a compound where the 8- or9-membered bicyclic heterocyclic is substituted with one R^(2c1) whichis hydrogen and a second R^(2c1) which is selected from hydrogen andC₁-C₆alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl.

Embodiment 65: Provided is a compound according to Formula (I) or (Ii),wherein

-   -   R^(2c) is a 5-membered monocyclic heteroaryl substituted with        R^(2c2) and optionally substituted with R^(2c3); R²⁰ is a 8- or        9-membered bicyclic heterocyclic optionally substituted with 1        or 2 R^(2c1); R^(2c) is a 8- or 9-membered bicyclic heterocyclic        substituted with R^(2c2) and optionally substituted with        R^(2c3); R²⁰ is a 6-membered monocyclic heteroaryl substituted        with R^(2c2) and optionally substituted with 1 or 2 R^(2c3); and        -   R^(2c2) is C₁-C₆alkylcarbonyl, —CN, —(CH₂)₀₋₁NH₂,            C₁-C₆alkoxy, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂,            —(CH₂)₀₋₁NHC(O)R^(2f), —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or            6-membered monocyclic heteroaryl, or 9- or 10-membered            bicyclic heteroaryl; wherein R^(2f) is C₁-C₆alkyl,            C₃-C₆cycloalkyl, or C₃-C₆cycloalkylC₁-C₃alkyl; and        -   R^(2c3) is independently H, halo, C₁-C₆alkyl, C₁-C₆alkoxy,            or C₃-C₈cycloalkyloxy;        -   each R^(2c1) is independently H, halo, C₁-C₆alkyl,            C₁-C₆alkylcarbonyl, C₁-C₆alkoxy, C₃-C₈cycloalkyloxy, —CN,            —(CH₂)₀₋₁NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂,            —(CH₂)₀₋₁NHC(O)R^(2f), —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or            6-membered monocyclic heteroaryl, or 9- or 10-membered            bicyclic heteroaryl; wherein R^(2f) is C₁-C₆alkyl,            C₃-C₆cycloalkyl, or C₃-C₆cycloalkylC₁-C₃alkyl;            and all other groups are as defined in the Summary or in            some or any embodiment provided herein, including any one of            Embodiments 55-63. In a subembodiment of Embodiment 65,            provided is a compound where R²⁰ is a 5-membered monocyclic            heteroaryl substituted with R^(2c2) and optionally            substituted with R^(2c3); 8-membered bicyclic heterocyclic            optionally substituted with 1 or 2 R^(2c1); R²⁰ is a            8-membered bicyclic heterocyclic substituted with R^(2c2)            and optionally substituted with R^(2c3); or R²⁰ is a            6-membered monocyclic heteroaryl substituted with R^(2c2)            and optionally substituted with 1 or 2 R^(2c3).

Embodiment 65a: In an embodiment of Embodiment 65, provided is acompound where each R^(2c1) is hydrogen (i.e. R^(2c) is notsubstituted); and all other groups are as defined in the Summary or insome or any embodiment provided herein, including any one of Embodiments55-63. In a subembodiment of Embodiment 65, provided is a compound whereone R^(2c1) is hydrogen and the other R^(2c1) is selected fromC₁-C₆alkylcarbonyl, —CN, —(CH₂)₀₋₁NH₂, and —(CH₂)₀₋₁NHC(O)R^(2f),—(CH₂)₀₋₁NHC(O)OR^(2f); wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl,or C₃-C₆cycloalkylC₁-C₃alkyl; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 55-63. In a subembodiment of Embodiment 65, provided is acompound where one R^(2c1) is hydrogen and the other R^(2c1) is —CN; andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 55-63.

Embodiment 65b: In an embodiment of Embodiment 65, provided is acompound where R^(2c2) is C₁-C₆alkylcarbonyl, —CN, —(CH₂)₀₋₁NH₂, or—(CH₂)₀₋₁NHC(O)R^(2f), —(CH₂)₀₋₁NHC(O)OR²f; wherein R^(2f) isC₁-C₆alkyl, C₃-C₆cycloalkyl, or C₃-C₆cycloalkylC₁-C₃alkyl; and all othergroups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 55-63.

Embodiment 65c: In an embodiment of Embodiment 65 or 65b, provided is acompound where each R^(2c3) is hydrogen; and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 55-63.

Embodiment 65d: In a subembodiment of Embodiment 65, 65b, or 65c,provided is a compound where R^(2c) is pyrazolyl, pyridinyl, or2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is substitutedwith R^(2c2) and optionally substituted with R^(2c3); and all othergroups are as defined in the Summary or in some or any embodimentprovided herein, including any one of Embodiments 55-63. In asubembodiment of Embodiment 65, 65b, or 65c, provided is a compoundwhere R^(2c) is a 5-membered monocyclic heteroaryl substituted withR^(2c2) and optionally substituted with R^(2c3). In a subembodiment ofEmbodiment 65, 65b, or 65c, provided is a compound where R^(2c) is a8-membered bicyclic heterocyclic substituted with R^(2c2) and optionallysubstituted with R^(2c3). In a subembodiment of Embodiment 65, 65b, or65c, provided is a compound where R^(2c) is a 6-membered monocyclicheteroaryl substituted with R^(2c2) and optionally substituted withR^(2c3).

Embodiment 65e: In an embodiment of Embodiment 65, provided is acompound where R^(2c) is pyrazolyl, preferably pyrazol-2-yl, substitutedR^(2c2) which is cyano and R^(2c3) is hydrogen; and all other groups areas defined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 55-63. In an embodiment of Embodiment65, provided is a compound where R^(2c) is pyridinyl, preferablypyridin-2-yl, substituted with R^(2c2) which is cyano and R^(2c3) ishydrogen; and all other groups are as defined in the Summary or in someor any embodiment provided herein, including any one of Embodiments55-63. In an embodiment of Embodiment 65, provided is a compound whereR^(2c) is 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, preferably2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, substituted with R^(2c2)where R^(2c2) is alkylcarbonyl, preferably, methylcarbonyl orethylcarbonyl and where R^(2c3) is hydrogen; and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 55-63.

Embodiment 65f: In an embodiment of Embodiment 65, provided is acompound where R^(2c) is a 8- or 9-membered bicyclic heterocyclicoptionally substituted with 1 or 2 R^(2c1); and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 55-63.

Embodiment 65f-1: In a sub-embodiment of Embodiment 65f, provided is acompound where the 8- or 9-membered bicyclic heterocyclic (optionallysubstituted with 1 or 2 R^(2c1)) is a 5-membered heteroaryl group,preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferablyforming an 8-membered bicyclic heterocyclic, which is optionallysubstituted with 1 or 2 R^(2c1).

Embodiment 65f-2: In a sub-embodiment of Embodiment 65f, provided is acompound where the 8- or 9-membered bicyclic heterocyclic (optionallysubstituted with 1 or 2 R^(2c1)) is a 5-membered heteroaryl group,preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferablyforming an 8-membered bicyclic heterocyclic group, which is optionallysubstituted with 1 or 2 R^(2c1); and where the rest of the molecule isattached to the 5-membered heteroaryl group fused to the nonaromaticcyclic group through the 5-membered heteroaryl portion.

Embodiment 65f-3: In a sub-embodiment of any one of Embodiments 65f,65f-1, and 65f-2, provided is a compound where the nonaromatic portionof the 8- or 9-membered bicyclic heterocyclic (optionally substitutedwith 1 or 2 R^(2c1)) comprises a heteroatom in the ring, preferablynitrogen.

Embodiment 65f-4: In a sub-embodiment of any one of Embodiments 65f,65f-1, 65f-2, and 65f-3, provided is a compound where the 8- or9-membered bicyclic heterocyclic is substituted with one R^(2c1) whichis hydrogen and a second R^(2c1) which is selected from hydrogen andC₁-C₆alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl.

Embodiment 65g: In an embodiment of Embodiment 65, provided is acompound where R², is a 8- or 9-membered bicyclic heterocyclicsubstituted with R^(2c2) and optionally substituted with R^(2c3); andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 55-63.

Embodiment 65g-1: In a sub-embodiment of Embodiment 65g, provided is acompound where the 8- or 9-membered bicyclic heterocyclic (substitutedwith R^(2c2) and optionally substituted with R^(2c3)) is a 5-memberedheteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclicgroup, preferably forming an 8-membered bicyclic heterocyclic, which issubstituted with R^(2c2) and optionally substituted with R^(2c3).

Embodiment 65g-2: In a sub-embodiment of Embodiment 65g, provided is acompound where the 8- or 9-membered bicyclic heterocyclic (substitutedwith R^(2c2) and optionally substituted with R^(2c3)) is a 5-memberedheteroaryl group, preferably a pyrazolyl, fused to a nonaromatic cyclicgroup, preferably forming an 8-membered bicyclic heterocyclic group,which is substituted with R^(2c2) and optionally substituted withR^(2c3); and where the rest of the molecule is attached to the5-membered heteroaryl group fused to the nonaromatic cyclic groupthrough the 5-membered heteroaryl portion.

Embodiment 65g-3: In a sub-embodiment of any one of Embodiments 65g,65g-1, and 65g-2, provided is a compound where the nonaromatic portionof the 8- or 9-membered bicyclic heterocyclic (substituted with R^(2c2)and optionally substituted with R^(2c3)) comprises a heteroatom in thering, preferably nitrogen.

Embodiment 65g-4: In a sub-embodiment of any one of Embodiments 65g,65g-1, 65g-2, and 65g-3, provided is a compound where the 8- or9-membered bicyclic heterocyclic is substituted with C₁-C₆alkylcarbonyl,preferably methylcarbonyl or ethylcarbonyl, and R^(2c3) is hydrogen.

Embodiment 66: Provided is a compound according to Formula (I) or (Ij),wherein

-   -   R^(2c) is a 5-membered monocyclic heteroaryl optionally        substituted with 1 or 2 R^(2c1); a 8- or 9-membered bicyclic        heterocyclic optionally substituted with 1 or 2 R^(2c1); or a        6-membered monocyclic heteroaryl optionally substituted with 1,        2, or 3 R^(2c1); and        -   each R^(2c1) is independently H, halo, C₁-C₆alkyl,            C₁-C₆alkylcarbonyl, —CN, C₁-C₆alkoxy, C₃-C₈cycloalkyloxy,            —(CH₂)₀₋₁NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂,            —(CH₂)₀₋₁NHC(O)R², —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or 6-membered            monocyclic heteroaryl, or 9- or 10-membered bicyclic            heteroaryl; wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl,            or C₃-C₆cycloalkylC₁-C₃alkyl;            and all other groups are as defined in the Summary or in            some or any embodiment provided herein, including any one of            Embodiments 55-63. In a subembodiment of Embodiment 66,            provided is a compound where R^(2c) is a 5-membered            monocyclic heteroaryl optionally substituted with 1 or 2            R^(2c1); R^(2c) is a 8-membered bicyclic heterocyclic            optionally substituted with 1 or 2 R^(2c1); or R^(2c) is a            6-membered monocyclic heteroaryl optionally substituted with            1, 2, or 3 R^(2c1).

Embodiment 66a: In an embodiment of Embodiment 66, provided is acompound where each R^(2c1) is hydrogen (i.e. R^(2c) is notsubstituted); and all other groups are as defined in the Summary or insome or any embodiment provided herein, including any one of Embodiments55-63. In a subembodiment of Embodiment 66, provided is a compound whereone R^(2c1) is hydrogen and the other R^(2c1) is selected fromC₁-C₆alkylcarbonyl, —CN, —(CH₂)₀₋₁NH₂, and —(CH₂)₀₋₁NHC(O)R^(2f),—(CH₂)₀₋₁NHC(O)OR^(2f); wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl,or C₃-C₆cycloalkylC₁-C₃alkyl; and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 55-63. In a subembodiment of Embodiment 66, provided is acompound where one R^(2c1) is hydrogen and the other R^(2c1) is —CN; andall other groups are as defined in the Summary or in some or anyembodiment provided herein, including any one of Embodiments 55-63.

Embodiment 66b: In a subembodiment of Embodiment 66 or 66a, provided isa compound where R^(2c) is pyrazolyl, pyridinyl, or2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, each of which is optionallysubstituted with 1 or 2 R^(2c1). In a subembodiment of Embodiment 66 or66a, provided is a compound where R^(2c) is a 5-membered monocyclicheteroaryl optionally substituted with 1 or 2 R^(2c1). In asubembodiment of Embodiment 66 or 66a, provided is a compound whereR^(2c) is a 8-membered bicyclic heterocyclic optionally substituted with1 or 2 R^(2c1). In a subembodiment of Embodiment 66 or 66a, provided isa compound where R^(2c) is a 6-membered monocyclic heteroaryl optionallysubstituted with 1, 2, or 3 R^(2c1).

Embodiment 66c: In an embodiment of Embodiment 66, provided is acompound where R^(2c) is pyrazolyl, preferably pyrazol-2-yl, and isunsubstituted (i.e. both R^(2c1) are hydrogen) or is substituted withone R^(2c1) which is preferably cyano (i.e. the other R^(2c1) ishydrogen); and all other groups are as defined in the Summary or in someor any embodiment provided herein, including any one of Embodiments55-63. In an embodiment of Embodiment 66, provided is a compound whereR^(2c) is pyridinyl, preferably pyridin-2-yl, and is unsubstituted (i.e.both R^(2c1) are hydrogen) or is substituted with one R^(2c1) which iscyano (i.e. the other R^(2c1) is hydrogen); and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 55-63. In an embodiment of Embodiment66, provided is a compound where R^(2c) is2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, preferably2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-2-yl, and is unsubstituted (i.e.both R^(2c1) are hydrogen) or is substituted with one R^(2c1) (i.e. theother R^(2c1) is hydrogen) where the one R^(2c1) is alkylcarbonyl,preferably, methylcarbonyl or ethylcarbonyl; and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 55063.

Embodiment 66d: In an embodiment of Embodiment 66 or 66a, provided is acompound where R^(2c) is a 8- or 9-membered bicyclic heterocyclicoptionally substituted with 1 or 2 R^(2c1); and all other groups are asdefined in the Summary or in some or any embodiment provided herein,including any one of Embodiments 55-63.

Embodiment 66d-1: In a sub-embodiment of Embodiment 66d, provided is acompound where the 8- or 9-membered bicyclic heterocyclic (optionallysubstituted with 1 or 2 R^(2c1)) is a 5-membered heteroaryl group,preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferablyforming an 8-membered bicyclic heterocyclic, which is optionallysubstituted with 1 or 2 R^(2c1).

Embodiment 66d-2: In a sub-embodiment of Embodiment 66d, provided is acompound where the 8- or 9-membered bicyclic heterocyclic (optionallysubstituted with 1 or 2 R^(2c1)) is a 5-membered heteroaryl group,preferably a pyrazolyl, fused to a nonaromatic cyclic group, preferablyforming an 8-membered bicyclic heterocyclic group, which is optionallysubstituted with 1 or 2 R^(2c1); and where the rest of the molecule isattached to the 5-membered heteroaryl group fused to the nonaromaticcyclic group through the 5-membered heteroaryl portion.

Embodiment 66d-3: In a sub-embodiment of any one of Embodiments 66d,66d-1, and 66d-2, provided is a compound where the nonaromatic portionof the 8- or 9-membered bicyclic heterocyclic (optionally substitutedwith 1 or 2 R^(2c1)) comprises a heteroatom in the ring, preferablynitrogen.

Embodiment 66d-4: In a sub-embodiment of any one of Embodiments 66d,66d-1, 66d-2, and 66d-3, provided is a compound where the 8- or9-membered bicyclic heterocyclic is substituted with one R^(2c1) whichis hydrogen and a second R^(2c1) which is selected from hydrogen andC₁-C₆alkylcarbonyl, preferably methylcarbonyl or ethylcarbonyl.

Embodiment 67: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein one X¹ is C(CH₂R^(2c)), and the other two X¹ areeach CR^(2e); and all other groups are as defined in the Summary or insome or any embodiment provided herein, including any one of Embodiments52 to 66d-4. In a sub-embodiment, each CR^(2e) is CH. In asub-embodiment, C(CH₂R^(2c)) is in the meta-position with respect toR^(2d).

Embodiment 68: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein one X¹ is C(CH₂R^(2c)), the second X¹ is N, andthe third X¹ is CR^(2e); and all other groups are as defined in theSummary or in some or any embodiment provided herein, including any oneof Embodiments 52 to 66d-4. In a sub-embodiment, CR^(2e) is CH. In asub-embodiment, C(CH₂R^(2c)) is in the meta-position with respect toR^(2d).

Embodiment 69: Provided is a compound according to Formula (I), (Ih),(Ii), or (Ij), wherein one X¹ is C(CH₂R^(2c)), and the other two X¹ areeach N; and all other groups are as defined in the Summary or in some orany embodiment provided herein, including any one of Embodiments 52 to66d-4. In a sub-embodiment, C(CH₂R^(2c)) is in the meta-position withrespect to R^(2d).

Embodiment 70: Provided is a pharmaceutical composition comprising aCompound of any one of Embodiments 52-69 or a stereoisomer, a mixture ofstereoisomers, and/or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier.

Embodiment 71: Provided is a method of treating a condition, disease, ordisorder by inhibiting MYST family of lysine acetyl transferases,including Kat6a and Kat6b, comprising administering to a patient in needthereof a therapeutically effective amount of the Compound of any one ofEmbodiments 52-69 or a stereoisomer, a mixture of stereoisomers, and/ora pharmaceutically acceptable salt thereof or a therapeuticallyeffective amount of the composition of Embodiment 70.

Embodiment 72: Provided is the method of embodiment 71 where thecondition, disease, or disorder is a hyperproliferative disease, such ascancer. In some or any embodiments, the cancer is a particular typeselected from: lymphoma, melanoma, carcinoma (e.g. adenocarcinoma,hepatocellular carcinoma, medullary carcinoma, papillary carcinoma,squamous cell carcinoma), astrocytoma, glioma, medulloblastoma, myeloma,meningioma, neuroblastoma, and sarcoma (e.g. angiosarcoma,chrondrosarcoma, osteosarcoma). In some or any embodiments, the cancermay be a MYST overexpressing cancer; the cancer may over-express MYSTprotein relative to non-cancerous tissue; the cancer may overproduceMYST mRNA relative to non-cancerous tissue; the cancer may be a MYSToverexpressing cancer where the overexpressed MYST protein or MYST mRNAmay be any one of KATs of the MYST family, e.g. KAT6A. In some or anyembodiments, the cancer is selected from one or more of the followingleukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia(AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia(CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lungcancer, melanoma, breast cancer, breast ductal carcinoma, colon andrectal cancer, colon cancer, squamous cell carcinoma, gastric cancer,adrenocortical cancer, anal cancer, bladder cancer, blood cancer, bonecancer, brain tumor, cancer of the female genital system, cancer of themale genital system (including testicular cancer and penile cancer),central nervous system lymphoma, cervical cancer, childhoodrhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrialsarcoma, esophageal cancer, eye cancer, gallbladder cancer,gastrointestinal tract cancer, hairy cell leukemia, head and neckcancer, hepatocellular cancer, hypopharyngeal cancer, Kaposi's sarcoma,kidney cancer, laryngeal cancer, liver cancer, malignant fibroushistiocytoma, malignant thymoma, mesothelioma, multiple myeloma,myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,nervous system cancer, neuroblastoma, oral cavity cancer, oropharyngealcancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroidcancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm,primary CNS lymphoma, rectal cancer, respiratory system, retinoblastoma,salivary gland cancer, skin cancer, small intestine cancer, soft tissuesarcoma, stomach cancer, testicular cancer, thyroid cancer, urinarysystem cancer, uterine cancer, uterine sarcoma, vaginal cancer,endocrine, neoplasms of the central nervous system (CNS), primary CNSlymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitaryadenoma, vascular system, Waldenstrom's macroglobulinemia and/or Wilms'tumor. In some or any embodiments, the cancer is breast cancer,including ER positive breast cancer, non-small cell lung cancer,prostate cancer, pancreatic cancer, ovarian cancer, or blood cancer(including a leukemia or lymphoma).

In some embodiments, provided herein are:

-   -   (a) compounds as described herein, e.g., of Formula (I), (Ia),        (Ib), (Ic), (Id), (le), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1),        (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1),        Embodiments A, B and 1-72, and pharmaceutically acceptable salts        and compositions thereof;    -   (b) compounds as described herein, e.g., of Formula (I), (Ia),        (Ib), (Ic), (Id), (le), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1),        (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1),        Embodiments A, B and 1-72, and pharmaceutically acceptable salts        and compositions thereof for use in the treatment of a        condition, disease, or disorder by inhibiting MYST family of        lysine acetyl transferases, including KAT6A and KAT6B;    -   (c) processes for the preparation of compounds as described        herein, e.g., of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),        (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2),        (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B and 1-72, as        described in more detail elsewhere herein;    -   (d) pharmaceutical formulations comprising a compound as        described herein, e.g., of Formula (I), (Ia), (Ib), (Ic), (Id),        (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1),        (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B and        1-72, or a stereoisomer, a mixture of stereoisomers, and/or a        pharmaceutically acceptable salt thereof together with a        pharmaceutically acceptable carrier;    -   (e) a method for the treatment of a condition, disease, or        disorder by inhibiting MYST family of lysine acetyl        transferases, including KAT6A and KAT6B, in a subject that        includes the administration of an effective treatment amount of        a compound as described herein, e.g., of Formula (I), (Ia),        (Ib), (Ic), (Id), (le), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1),        (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1),        Embodiments A, B and 1-72, its pharmaceutically acceptable salt        or composition;    -   (f) pharmaceutical formulations comprising a compound as        described herein, e.g., of Formula (I), (Ia), (Ib), (Ic), (Id),        (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1),        (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1), Embodiments A, B and        1-72, or a stereoisomer, a mixture of stereoisomers, and/or a        pharmaceutically acceptable salt thereof together with one or        more other effective agents for treating a condition, disease,        or disorder by inhibiting MYST family of lysine acetyl        transferases, including KAT6A and KAT6B, optionally in a        pharmaceutically acceptable carrier; or    -   (g) a method for the treatment of a condition, disease, or        disorder by inhibiting MYST family of lysine acetyl        transferases, including KAT6A and KAT6B, in a subject that        includes the administration of an effective treatment amount of        a compound as described herein, e.g., of Formula (I), (Ia),        (Ib), (Ic), (Id), (le), (If), (Ig), (Ih), (Ii), (Ij), (Ia-1),        (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1), (If-1), or (Ig-1),        Embodiments A, B and 1-72, its pharmaceutically acceptable salt        or composition in combination and/or alternation with one or        more agent for the treatment of a condition, disease, or        disorder by inhibiting MYST family of lysine acetyl        transferases, including KAT6A and KAT6B.

Optically Active Compounds

It is appreciated that compounds provided herein have several chiralcenters and may exist in and be isolated in optically active and racemicforms. It is to be understood that any racemic, optically-active,diastereomeric, tautomeric, or stereoisomeric form, or mixtures thereof,of a compound provided herein, which possess the useful propertiesdescribed herein is within the scope of the invention. It being wellknown in the art how to prepare optically active forms (in certainembodiments, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

In some or any embodiments, the term “stereoisomers” includesdiastereomers, enantiomers, rotamers, atropisomers, regioisomers, andgeometric isomers; and mixtures thereof.

In certain embodiments, methods to obtain optically active materials areknown in the art, and include at least the following.

-   -   i) physical separation of crystals—a technique whereby        macroscopic crystals of the individual stereoisomers are        manually separated. This technique can be used if crystals of        the separate stereoisomers exist, i.e., the material is a        conglomerate, and the crystals are visually distinct;    -   ii) simultaneous crystallization—a technique whereby the        individual stereoisomers are separately crystallized from a        solution of the racemate, possible only if the latter is a        conglomerate in the solid state;    -   iii) enzymatic resolutions—a technique whereby partial or        complete separation of a racemate by virtue of differing rates        of reaction for the stereoisomers with an enzyme;    -   iv) enzymatic asymmetric synthesis—a synthetic technique whereby        at least one step of the synthesis uses an enzymatic reaction to        obtain an stereoisomerically pure or enriched synthetic        precursor of the desired stereoisomer;    -   v) chemical asymmetric synthesis—a synthetic technique whereby        the desired stereoisomer is synthesized from an achiral        precursor under conditions that produce asymmetry (i.e.,        chirality) in the product, which may be achieved using chiral        catalysts or chiral auxiliaries;    -   vi) diastereomer separations—a technique whereby a racemic        compound is reacted with an enantiomerically pure reagent (the        chiral auxiliary) that converts the individual enantiomers to        diastereomers. The resulting diastereomers are then separated by        chromatography or crystallization by virtue of their now more        distinct structural differences and the chiral auxiliary later        removed to obtain the desired enantiomer;    -   vii) first- and second-order asymmetric transformations—a        technique whereby diastereomers from the racemate equilibrate to        yield a preponderance in solution of the diastereomer from the        desired enantiomer or where preferential crystallization of the        diastereomer from the desired enantiomer perturbs the        equilibrium such that eventually in principle all the material        is converted to the crystalline diastereomer from the desired        enantiomer. The desired enantiomer is then released from the        diastereomer;    -   viii) kinetic resolutions—this technique refers to the        achievement of partial or complete resolution of a racemate (or        of a further resolution of a partially resolved compound) by        virtue of unequal reaction rates of the stereoisomers with a        chiral, non-racemic reagent or catalyst under kinetic        conditions;    -   ix) stereospecific synthesis from non-racemic precursors—a        synthetic technique whereby the desired stereoisomer is obtained        from non-chiral starting materials and where the stereochemical        integrity is not or is only minimally compromised over the        course of the synthesis;    -   x) chiral liquid chromatography—a technique whereby the        stereoisomers of a racemate are separated in a liquid mobile        phase by virtue of their differing interactions with a        stationary phase. The stationary phase can be made of chiral        material or the mobile phase can contain an additional chiral        material to provoke the differing interactions;    -   xi) chiral gas chromatography—a technique whereby the racemate        is volatilized and stereoisomers are separated by virtue of        their differing interactions in the gaseous mobile phase with a        column containing a fixed non-racemic chiral adsorbent phase;    -   xii) extraction with chiral solvents—a technique whereby the        stereoisomers are separated by virtue of preferential        dissolution of one stereoisomer into a particular chiral        solvent;    -   xiii) transport across chiral membranes—a technique whereby a        racemate is placed in contact with a thin membrane barrier. The        barrier typically separates two miscible fluids, one containing        the racemate, and a driving force such as concentration or        pressure differential causes preferential transport across the        membrane barrier. Separation occurs as a result of the        non-racemic chiral nature of the membrane which allows only one        stereoisomer of the racemate to pass through.

Isotopically Enriched Compounds

Also provided herein are isotopically enriched compounds, including butnot limited to isotopically enriched di-substituted pyrazoles.

Isotopic enrichment (in certain embodiments, deuteration) ofpharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics(“PD”), and toxicity profiles, has been demonstrated previously withsome classes of drugs. See, for example, Lijinsky et. al., Food Cosmet.Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et al., Mutation Res. 308: 33 (1994); Gordon etal., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43:487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem.Biol. Interact. 117: 191 (1999).

Isotopic enrichment of a drug can be used, in certain embodiments, to(1) reduce or eliminate unwanted metabolites, (2) increase the half-lifeof the parent drug, (3) decrease the number of doses needed to achieve adesired effect, (4) decrease the amount of a dose necessary to achieve adesired effect, (5) increase the formation of active metabolites, if anyare formed, and/or (6) decrees the production of deleterious metabolitesin specific tissues and/or create a more effective drug and/or a saferdrug for combination therapy, whether the combination therapy isintentional or not.

Replacement of an atom for one of its isotopes often will result in achange in the reaction rate of a chemical reaction. This phenomenon isknown as the Kinetic Isotope Effect (“KIE”). For example, if a C—H bondis broken during a rate-determining step in a chemical reaction (i.e.the step with the highest transition state energy), substitution of adeuterium for that hydrogen will cause a decrease in the reaction rateand the process will slow down. This phenomenon is known as theDeuterium Kinetic Isotope Effect (“DKIE”). See, e.g., Foster et al.,Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J.Physiol. Pharmacol., vol. 77, pp. 79-88 (1999).

The magnitude of the DKIE can be expressed as the ratio between therates of a given reaction in which a C—H bond is broken, and the samereaction where deuterium is substituted for hydrogen. The DKIE can rangefrom about 1 (no isotope effect) to very large numbers, such as 50 ormore, meaning that the reaction can be fifty, or more, times slower whendeuterium is substituted for hydrogen. High DKIE values may be due inpart to a phenomenon known as tunneling, which is a consequence of theuncertainty principle. Tunneling is ascribed to the small mass of ahydrogen atom, and occurs because transition states involving a protoncan sometimes form in the absence of the required activation energy.Because deuterium has more mass than hydrogen, it statistically has amuch lower probability of undergoing this phenomenon.

Tritium (“T”) is a radioactive isotope of hydrogen, used in research,fusion reactors, neutron generators and radiopharmaceuticals. Tritium isa hydrogen atom that has 2 neutrons in the nucleus and has an atomicweight close to 3. It occurs naturally in the environment in very lowconcentrations, most commonly found as T₂O. Tritium decays slowly(half-life=12.3 years) and emits a low energy beta particle that cannotpenetrate the outer layer of human skin. Internal exposure is the mainhazard associated with this isotope, yet it must be ingested in largeamounts to pose a significant health risk. As compared with deuterium, alesser amount of tritium must be consumed before it reaches a hazardouslevel. Substitution of tritium (“T”) for hydrogen results in yet astronger bond than deuterium and gives numerically larger isotopeeffects. Similarly, substitution of isotopes for other elements,including, but not limited to, ¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶Sfor sulfur, ¹⁵N for nitrogen, and ¹⁷O or ¹⁸O for oxygen, may lead to asimilar kinetic isotope effect.

For example, the DKIE was used to decrease the hepatotoxicity ofhalothane by presumably limiting the production of reactive species suchas trifluoroacetyl chloride. However, this method may not be applicableto all drug classes. For example, deuterium incorporation can lead tometabolic switching. The concept of metabolic switching asserts thatxenogens, when sequestered by Phase I enzymes, may bind transiently andre-bind in a variety of conformations prior to the chemical reaction(e.g., oxidation). This hypothesis is supported by the relatively vastsize of binding pockets in many Phase I enzymes and the promiscuousnature of many metabolic reactions. Metabolic switching can potentiallylead to different proportions of known metabolites as well as altogethernew metabolites. This new metabolic profile may impart more or lesstoxicity.

The animal body expresses a variety of enzymes for the purpose ofeliminating foreign substances, such as therapeutic agents, from itscirculation system. In certain embodiments, such enzymes include thecytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases,dehydrogenases, and monoamine oxidases, to react with and convert theseforeign substances to more polar intermediates or metabolites for renalexcretion. Some of the most common metabolic reactions of pharmaceuticalcompounds involve the oxidation of a carbon-hydrogen (C—H) bond toeither a carbon-oxygen (C—O) or carbon-carbon (C—C) pi-bond. Theresultant metabolites may be stable or unstable under physiologicalconditions, and can have substantially different pharmacokinetic,pharmacodynamic, and acute and long-term toxicity profiles relative tothe parent compounds. For many drugs, such oxidations are rapid. Thesedrugs therefore often require the administration of multiple or highdaily doses.

Therefore, isotopic enrichment at certain positions of a compoundprovided herein will produce a detectable KIE that will affect thepharmacokinetic, pharmacologic, and/or toxicological profiles of acompound provided herein in comparison with a similar compound having anatural isotopic composition.

Pharmaceutical Compositions and Methods of Administration

The compounds provided herein can be formulated into pharmaceuticalcompositions using methods available in the art and those disclosedherein. Any of the compounds disclosed herein can be provided in theappropriate pharmaceutical composition and be administered by a suitableroute of administration.

The methods provided herein encompass administering pharmaceuticalcompositions containing at least one compound as described herein,including a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1), (Ie-1),(If-1), or (Ig-1), Embodiments A, B and 1-72, if appropriate in a saltform, either used alone or in the form of a combination with one or morecompatible and pharmaceutically acceptable carriers, such as diluents oradjuvants, or with another agent for the treatment of a condition,disease, or disorder by inhibiting MYST family of lysine acetyltransferases, including KAT6A and KAT6B.

In certain embodiments, the second agent can be formulated or packagedwith the compound provided herein. The second agent will only beformulated with the compound provided herein when, according to thejudgment of those of skill in the art, such co-formulation should notinterfere with the activity of either agent or the method ofadministration. In certain embodiments, the compound provided herein andthe second agent are formulated separately. They can be packagedtogether, or packaged separately, for the convenience of thepractitioner of skill in the art.

In clinical practice the active agents provided herein may beadministered by any conventional route, in particular orally,parenterally, rectally or by inhalation (e.g. in the form of aerosols).In certain embodiments, the compound provided herein is administeredorally.

Use may be made, as solid compositions for oral administration, oftablets, pills, hard gelatin capsules, powders or granules. In thesecompositions, the active product is mixed with one or more inertdiluents or adjuvants, such as sucrose, lactose or starch.

These compositions can comprise substances other than diluents, forexample a lubricant, such as magnesium stearate, or a coating intendedfor controlled release.

Use may be made, as liquid compositions for oral administration, ofsolutions which are pharmaceutically acceptable, suspensions, emulsions,syrups and elixirs containing inert diluents, such as water or liquidparaffin. These compositions can also comprise substances other thandiluents, in certain embodiments, wetting, sweetening or flavoringproducts.

The compositions for parenteral administration can be emulsions orsterile solutions. Use may be made, as solvent or vehicle, of propyleneglycol, a polyethylene glycol, vegetable oils, in particular olive oil,or injectable organic esters, in certain embodiments, ethyl oleate.These compositions can also contain adjuvants, in particular wetting,isotonizing, emulsifying, dispersing and stabilizing agents.Sterilization can be carried out in several ways, in certainembodiments, using a bacteriological filter, by radiation or by heating.They can also be prepared in the form of sterile solid compositionswhich can be dissolved at the time of use in sterile water or any otherinjectable sterile medium.

The compositions for rectal administration are suppositories or rectalcapsules which contain, in addition to the active principle, excipientssuch as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions can also be aerosols. For use in the form of liquidaerosols, the compositions can be stable sterile solutions or solidcompositions dissolved at the time of use in apyrogenic sterile water,in saline or any other pharmaceutically acceptable vehicle. For use inthe form of dry aerosols intended to be directly inhaled, the activeprinciple is finely divided and combined with a water-soluble soliddiluent or vehicle, in certain embodiments, dextran, mannitol orlactose.

In certain embodiments, a composition provided herein is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and single unit dosage forms provided herein comprise aprophylactically or therapeutically effective amount of one or moreprophylactic or therapeutic agents (e.g., a compound provided herein, orother prophylactic or therapeutic agent), and a typically one or morepharmaceutically acceptable carriers. In a specific embodiment and inthis context, the term “pharmaceutically acceptable” means approved by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopeia or other generally recognized pharmacopeia for use inanimals, and more particularly in humans. The term “carrier” includes adiluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)),excipient, or vehicle with which the therapeutic is administered. Anyembodiment described for “excipient”. Such pharmaceutical carriers canbe sterile liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. Water can be used asa carrier when the pharmaceutical composition is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid carriers, particularly forinjectable solutions. Examples of suitable pharmaceutical carriers aredescribed in Remington: The Science and Practice of Pharmacy;Pharmaceutical Press; 22 edition (Sep. 15, 2012).

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well-known to those skilled inthe art of pharmacy, and in certain embodiments, suitable excipientsinclude starch, glucose, lactose, sucrose, gelatin, malt, rice, flour,chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a subjectand the specific active ingredients in the dosage form. The compositionor single unit dosage form, if desired, can also contain minor amountsof wetting or emulsifying agents, or pH buffering agents.

Lactose free compositions provided herein can comprise excipients thatare well known in the art and are listed, in certain embodiments, in theU.S. Pharmacopeia (USP 36-NF 31 S2). In general, lactose freecompositions comprise an active ingredient, a binder/filler, and alubricant in pharmaceutically compatible and pharmaceutically acceptableamounts. Exemplary lactose free dosage forms comprise an activeingredient, microcrystalline cellulose, pre gelatinized starch, andmagnesium stearate.

Further encompassed herein are anhydrous pharmaceutical compositions anddosage forms comprising active ingredients, since water can facilitatethe degradation of some compounds. For example, the addition of water(e.g., 5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long term storage in order to determine characteristics suchas shelf life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, New York, 1995, pp. 379 80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms provided hereincan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine can be anhydrousif substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits. Incertain embodiments, suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

Further provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

The pharmaceutical compositions and single unit dosage forms can takethe form of solutions, suspensions, emulsion, tablets, pills, capsules,powders, sustained-release formulations and the like. Oral formulationcan include standard carriers such as pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc. Such compositions and dosage forms willcontain a prophylactically or therapeutically effective amount of aprophylactic or therapeutic agent, in certain embodiments, in purifiedform, together with a suitable amount of carrier so as to provide theform for proper administration to the subject. The formulation shouldsuit the mode of administration. In a certain embodiment, thepharmaceutical compositions or single unit dosage forms are sterile andin suitable form for administration to a subject, in certainembodiments, an animal subject, such as a mammalian subject, in certainembodiments, a human subject.

A pharmaceutical composition is formulated to be compatible with itsintended route of administration. In certain embodiments, routes ofadministration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, intramuscular, subcutaneous,oral, buccal, sublingual, inhalation, intranasal, transdermal, topical,transmucosal, intra-tumoral, intra-synovial and rectal administration.In a specific embodiment, the composition is formulated in accordancewith routine procedures as a pharmaceutical composition adapted forintravenous, subcutaneous, intramuscular, oral, intranasal or topicaladministration to human beings. In an embodiment, a pharmaceuticalcomposition is formulated in accordance with routine procedures forsubcutaneous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition may also include a solubilizingagent and a local anesthetic such as lignocamne to ease pain at the siteof the injection.

In certain embodiments, dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; ointments;cataplasms (poultices); pastes; powders; dressings; creams; plasters;solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels;liquid dosage forms suitable for oral or mucosal administration to asubject, including suspensions (e.g., aqueous or non-aqueous liquidsuspensions, oil in water emulsions, or a water in oil liquidemulsions), solutions, and elixirs; liquid dosage forms suitable forparenteral administration to a subject; and sterile solids (e.g.,crystalline or amorphous solids) that can be reconstituted to provideliquid dosage forms suitable for parenteral administration to a subject.

The composition, shape, and type of dosage forms provided herein willtypically vary depending on their use. In certain embodiments, a dosageform used in the initial treatment of viral infection may contain largeramounts of one or more of the active ingredients it comprises than adosage form used in the maintenance treatment of the same infection.Similarly, a parenteral dosage form may contain smaller amounts of oneor more of the active ingredients it comprises than an oral dosage formused to treat the same disease or disorder. These and other ways inwhich specific dosage forms encompassed herein will vary from oneanother will be readily apparent to those skilled in the art. See, e.g.,Remington: The Science and Practice of Pharmacy; Pharmaceutical Press;22 edition (Sep. 15, 2012).

Generally, the ingredients of compositions are supplied eitherseparately or mixed together in unit dosage form, in certainembodiments, as a dry lyophilized powder or water free concentrate in ahermetically sealed container such as an ampoule or sachet indicatingthe quantity of active agent. Where the composition is to beadministered by infusion, it can be dispensed with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where thecomposition is administered by injection, an ampoule of sterile waterfor injection or saline can be provided so that the ingredients may bemixed prior to administration.

Typical dosage forms comprise a compound provided herein, or apharmaceutically acceptable salt, solvate or hydrate thereof lie withinthe range of from about 0.1 mg to about 1000 mg per day, given as asingle once-a-day dose in the morning or as divided doses throughout theday taken with food. Particular dosage forms can have about 0.1, 0.2,0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100,200, 250, 500 or 1000 mg of the active compound.

Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be presented as discrete dosage forms, such as, but are not limitedto, tablets (e.g., chewable tablets), caplets, capsules, and liquids(e.g., flavored syrups). Such dosage forms contain predetermined amountsof active ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington: The Scienceand Practice of Pharmacy; Pharmaceutical Press; 22 edition (Sep. 15,2012).

In certain embodiments, the oral dosage forms are solid and preparedunder anhydrous conditions with anhydrous ingredients, as described indetail herein. However, the scope of the compositions provided hereinextends beyond anhydrous, solid oral dosage forms. As such, furtherforms are described herein.

Typical oral dosage forms are prepared by combining the activeingredient(s) in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. In certain embodiments,excipients suitable for use in oral liquid or aerosol dosage formsinclude, but are not limited to, water, glycols, oils, alcohols,flavoring agents, preservatives, and coloring agents. In certainembodiments, excipients suitable for use in solid oral dosage forms(e.g., powders, tablets, capsules, and caplets) include, but are notlimited to, starches, sugars, micro crystalline cellulose, diluents,granulating agents, lubricants, binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or non-aqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

In certain embodiments, a tablet can be prepared by compression ormolding. Compressed tablets can be prepared by compressing in a suitablemachine the active ingredients in a free flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

In certain embodiments, excipients that can be used in oral dosage formsinclude, but are not limited to, binders, fillers, disintegrants, andlubricants. Binders suitable for use in pharmaceutical compositions anddosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208,2906, 2910), microcrystalline cellulose, and mixtures thereof.

In certain embodiments, fillers suitable for use in the pharmaceuticalcompositions and dosage forms disclosed herein include, but are notlimited to, talc, calcium carbonate (e.g., granules or powder),microcrystalline cellulose, powdered cellulose, dextrates, kaolin,mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, andmixtures thereof. The binder or filler in pharmaceutical compositions istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

In certain embodiments, suitable forms of microcrystalline celluloseinclude, but are not limited to, the materials sold as AVICEL PH 101,AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMCCorporation, American Viscose Division, Avicel Sales, Marcus Hook, PA),and mixtures thereof. A specific binder is a mixture of microcrystallinecellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581.Suitable anhydrous or low moisture excipients or additives includeAVICEL PH 103™ and Starch 1500 LM.

Disintegrants are used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients should be used to form solid oral dosage forms.The amount of disintegrant used varies based upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. Typical pharmaceutical compositions comprise from about 0.5 toabout 15 weight percent of disintegrant, specifically from about 1 toabout 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, pre gelatinized starch, other starches, clays, otheralgins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, in certain embodiments, a syloid silicagel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by CabotCo. of Boston, MA), and mixtures thereof. If used at all, lubricants aretypically used in an amount of less than about 1 weight percent of thepharmaceutical compositions or dosage forms into which they areincorporated.

Delayed Release Dosage Forms

Active ingredients such as the compounds provided herein can beadministered by controlled release means or by delivery devices that arewell known to those of ordinary skill in the art. In certainembodiments, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556;5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891;5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350;6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548;6,613,358; and 6,699,500; each of which is incorporated herein byreference in its entirety. Such dosage forms can be used to provide slowor controlled release of one or more active ingredients using, incertain embodiments, hydropropylmethyl cellulose, other polymermatrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active ingredients provided herein. Thusencompassed herein are single unit dosage forms suitable for oraladministration such as, but not limited to, tablets, capsules, gel caps,and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designed controlledrelease preparation in medical treatment is characterized by a minimumof drug substance being employed to cure or control the condition,disease, or disorder in a minimum amount of time. Advantages ofcontrolled release formulations include extended activity of the drug,reduced dosage frequency, and increased subject compliance. In addition,controlled release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the drug may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In certain embodiments, a pump may beused (see, Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald etal., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574(1989)). In another embodiment, polymeric materials can be used. In yetanother embodiment, a controlled release system can be placed in asubject at an appropriate site determined by a practitioner of skill,i.e., thus requiring only a fraction of the systemic dose (see, e.g.,Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138(1984)). Other controlled release systems are discussed in the review byLanger (Science 249:1527-1533 (1990)). The active ingredient can bedispersed in a solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient in such parenteral compositions is highly dependent onthe specific nature thereof, as well as the needs of the subject.

Parenteral Dosage Forms

In certain embodiments, provided are parenteral dosage forms. Parenteraldosage forms can be administered to subjects by various routesincluding, but not limited to, subcutaneous, intravenous (includingbolus injection), intramuscular, and intra-arterial. Because theiradministration typically bypasses subjects' natural defenses againstcontaminants, parenteral dosage forms are typically, sterile or capableof being sterilized prior to administration to a subject. In certainembodiments, parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. In certain embodiments,suitable vehicles include, but are not limited to: Water for InjectionUSP; aqueous vehicles such as, but not limited to, Sodium ChlorideInjection, Ringer's Injection, Dextrose Injection, Dextrose and SodiumChloride Injection, and Lactated Ringer's Injection; water misciblevehicles such as, but not limited to, ethyl alcohol, polyethyleneglycol, and polypropylene glycol; and non-aqueous vehicles such as, butnot limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyloleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms.

Transdermal, Topical & Mucosal Dosage Forms

Also provided are transdermal, topical, and mucosal dosage forms.Transdermal, topical, and mucosal dosage forms include, but are notlimited to, ophthalmic solutions, sprays, aerosols, creams, lotions,ointments, gels, solutions, emulsions, suspensions, or other forms knownto one of skill in the art. See, e.g., Remington: The Science andPractice of Pharmacy; Pharmaceutical Press; 22 edition (Sep. 15, 2012);and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.Further, transdermal dosage forms include “reservoir type” or “matrixtype” patches, which can be applied to the skin and worn for a specificperiod of time to permit the penetration of a desired amount of activeingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed herein are well known to those skilled in thepharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3diol, isopropyl myristate, isopropyl palmitate, mineral oil, andmixtures thereof to form lotions, tinctures, creams, emulsions, gels orointments, which are nontoxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington: The Scienceand Practice of Pharmacy; Pharmaceutical Press; 22 edition (Sep. 15,2012).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients provided. In certain embodiments, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery enhancing orpenetration enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

Dosage and Unit Dosage Forms

In human therapeutics, the doctor will determine the posology which heconsiders most appropriate according to a preventive or curativetreatment and according to the age, weight, stage of the infection andother factors specific to the subject to be treated. In certainembodiments, doses are from about 1 to about 1000 mg per day for anadult, or from about 5 to about 250 mg per day or from about 10 to 50 mgper day for an adult. In certain embodiments, doses are from about 5 toabout 400 mg per day or 25 to 200 mg per day per adult. In certainembodiments, dose rates of from about 50 to about 500 mg per day arealso contemplated.

In further aspects, provided are methods of treating a condition,disease, or disorder by inhibiting MYST family of lysine acetyltransferases, including KAT6A and KAT6B, in a subject by administering,to a subject in need thereof, an effective amount of a compound providedherein, or a stereoisomer, a mixture of stereoisomers, and/or apharmaceutically acceptable salt thereof. The amount of the compound orcomposition which will be effective in the treatment of a disorder orone or more symptoms thereof will vary with the nature and severity ofthe condition, disease, or disorder, and the route by which the activeingredient is administered. The frequency and dosage will also varyaccording to factors specific for each subject depending on the specifictherapy (e.g., therapeutic or prophylactic agents) administered, theseverity of the disorder, disease, or condition, the route ofadministration, as well as age, body, weight, response, and the pastmedical history of the subject. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.

In certain embodiments, exemplary doses of a composition includemilligram or microgram amounts of the active compound per kilogram ofsubject or sample weight (e.g., about 10 micrograms per kilogram toabout 50 milligrams per kilogram, about 100 micrograms per kilogram toabout 25 milligrams per kilogram, or about 100 microgram per kilogram toabout 10 milligrams per kilogram). For compositions provided herein, incertain embodiments, the dosage administered to a subject is 0.140 mg/kgto 3 mg/kg of the subject's body weight, based on weight of the activecompound. In certain embodiments, the dosage administered to a subjectis between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50mg/kg of the subject's body weight.

In certain embodiments, the recommended daily dose range of acomposition provided herein for the condition, disease, or disorderdescribed herein lie within the range of from about 0.1 mg to about 1000mg per day, given as a single once-a-day dose or as divided dosesthroughout a day. In certain embodiments, the daily dose is administeredtwice daily in equally divided doses. In certain embodiments, a dailydose range should be from about 10 mg to about 200 mg per day, in otherembodiments, between about 10 mg and about 150 mg per day, in furtherembodiments, between about 25 and about 100 mg per day, in furtherembodiments, between about 100 and about 300 mg per day. It may benecessary to use dosages of the active ingredient outside the rangesdisclosed herein in some cases, as will be apparent to those of ordinaryskill in the art. Furthermore, it is noted that the clinician ortreating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with subject response.

Different therapeutically effective amounts may be applicable fordifferent conditions, diseases, or disorders, as will be readily knownby those of ordinary skill in the art. Similarly, amounts sufficient toprevent, manage, treat or ameliorate such disorders, but insufficient tocause, or sufficient to reduce, adverse effects associated with thecomposition provided herein are also encompassed by the herein describeddosage amounts and dose frequency schedules. Further, when a subject isadministered multiple dosages of a composition provided herein, not allof the dosages need be the same. In certain embodiments, the dosageadministered to the subject may be increased to improve the prophylacticor therapeutic effect of the composition or it may be decreased toreduce one or more side effects that a particular subject isexperiencing.

In certain embodiments, the daily dosage of the composition providedherein, based on weight of the active compound, administered to prevent,treat, manage, or ameliorate a condition, disorder, disease, or one ormore symptoms thereof in a subject is about 1 mg/kg, about 5 mg/kg,about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg,about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200mg/kg, about 225 mg/kg, about 250 mg/kg, about 275 mg/kg, about 300mg/kg, about 325 mg/kg, bout 350 mg/kg, about 375 mg/kg, about 400mg/kg, about 425 mg/kg, about 450 mg/kg, about 475 mg/kg, about 500mg/kg, or about 600 mg/kg. In certain embodiments, the daily dosage ofthe composition provided herein, based on weight of the active compound,administered to prevent, treat, manage, or ameliorate a condition,disorder, disease, or one or more symptoms thereof in a subject isbetween (inclusive) about 1-10 mg/kg, about 10 mg/kg, about 25-50 mg/kg,about 50-100 mg/kg, about 50-150 mg/kg, about 100-150 mg/kg, about100-200 mg/kg, about 150-200 mg/kg, about 150-250 mg/kg, about 250-300mg/kg, about 300-350 mg·kg, about 300-400 mg/kg, about 200-400 mg/kg,about 100-300 mg/kg, or about 400-500 mg/kg.

In certain embodiment, the twice daily dosage of the compositionprovided herein, based on weight of the active compound, administered toprevent, treat, manage, or ameliorate a condition, disorder, disease, orone or more symptoms thereof in a subject is about 1 mg/kg, about 5mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg,about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg,about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg,about 200 mg/kg, about 225 mg/kg, about 250 mg/kg, about 275 mg/kg, orabout 300 mg/kg. In certain embodiments, the twice daily dosage of thecomposition provided herein, based on weight of the active compound,administered to prevent, treat, manage, or ameliorate a condition,disorder, disease, or one or more symptoms thereof in a subject isbetween (inclusive) about 1-10 mg/kg, about 10 mg/kg, about 25-50 mg/kg,about 50-100 mg/kg, about 50-150 mg/kg, about 100-150 mg/kg, about100-200 mg/kg, about 150-200 mg/kg, or about 150-250 mg/kg

In certain embodiments, administration of the same composition may berepeated and the administrations may be separated by at least 2 hours, 4hours, 6 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, 10days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6months. In other embodiments, administration of the same prophylactic ortherapeutic agent may be repeated and the administration may beseparated by at least at least 4 hours, 6 hours, 8 hours, 12 hours, 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

In certain aspects, provided herein are unit dosages comprising acompound, or a stereoisomer, a mixture of stereoisomers, and/or apharmaceutically acceptable salt thereof, in a form suitable foradministration. Such forms are described in detail herein. In certainembodiments, the unit dosage comprises 1 to 1000 mg, 5 to 250 mg or 10to 50 mg active ingredient. In particular embodiments, the unit dosagescomprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg activeingredient. Such unit dosages can be prepared according to techniquesfamiliar to those of skill in the art.

In certain embodiments, dosages of the second agents to be used in acombination therapy are provided herein. In certain embodiments, dosageslower than those which have been or are currently being used to treat acondition, disease, or disorder by inhibiting MYST family of lysineacetyl transferases, including KAT6A and KAT6B, are used in thecombination therapies provided herein. The recommended dosages of secondagents can be obtained from the knowledge of those of skill in the art.For those second agents that are approved for clinical use, recommendeddosages are described in, for example, Hardman et al., eds., 1996,Goodman & Gilman's The Pharmacological Basis Of Therapeutics 9^(th) Ed,Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57^(th) Ed.,2003, Medical Economics Co., Inc., Montvale, NJ; which are incorporatedherein by reference in their entirety.

In various embodiments, the therapies (e.g., a compound provided hereinand the second agent) are administered less than 5 minutes apart, lessthan 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1to about 2 hours apart, at about 2 hours to about 3 hours apart, atabout 3 hours to about 4 hours apart, at about 4 hours to about 5 hoursapart, at about 5 hours to about 6 hours apart, at about 6 hours toabout 7 hours apart, at about 7 hours to about 8 hours apart, at about 8hours to about 9 hours apart, at about 9 hours to about 10 hours apart,at about 10 hours to about 11 hours apart, at about 11 hours to about 12hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hoursapart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hoursto 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hoursapart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96hours to 120 hours apart. In various embodiments, the therapies areadministered no more than 24 hours apart or no more than 48 hours apart.In certain embodiments, two or more therapies are administered withinthe same patient visit. In other embodiments, the compound providedherein and the second agent are administered concurrently.

In other embodiments, the compound provided herein and the second agentare administered at about 2 to 4 days apart, at about 4 to 6 days apart,at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeksapart.

In certain embodiments, administration of the same agent may be repeatedand the administrations may be separated by at least 1 day, 2 days, 3days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3months, or 6 months. In other embodiments, administration of the sameagent may be repeated and the administration may be separated by atleast at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days,45 days, 2 months, 75 days, 3 months, or 6 months.

In certain embodiments, a compound provided herein and a second agentare administered to a patient, in certain embodiments, a mammal, such asa human, in a sequence and within a time interval such that the compoundprovided herein can act together with the other agent to provide anincreased benefit than if they were administered otherwise. In certainembodiments, the second active agent can be administered at the sametime or sequentially in any order at different points in time; however,if not administered at the same time, they should be administeredsufficiently close in time so as to provide the desired therapeutic orprophylactic effect. In certain embodiments, the compound providedherein and the second active agent exert their effect at times whichoverlap. Each second active agent can be administered separately, in anyappropriate form and by any suitable route. In other embodiments, thecompound provided herein is administered before, concurrently or afteradministration of the second active agent.

In certain embodiments, the compound provided herein and the secondagent are cyclically administered to a patient. Cycling therapy involvesthe administration of a first agent (e.g., a first prophylactic ortherapeutic agent) for a period of time, followed by the administrationof a second agent and/or third agent (e.g., a second and/or thirdprophylactic or therapeutic agent) for a period of time and repeatingthis sequential administration. Cycling therapy can reduce thedevelopment of resistance to one or more of the therapies, avoid orreduce the side effects of one of the therapies, and/or improve theefficacy of the treatment.

In certain embodiments, the compound provided herein and the secondactive agent are administered in a cycle of less than about 3 weeks,about once every two weeks, about once every 10 days or about once everyweek. One cycle can comprise the administration of a compound providedherein and the second agent by infusion over about 90 minutes everycycle, about 1 hour every cycle, about 45 minutes every cycle. Eachcycle can comprise at least 1 week of rest, at least 2 weeks of rest, atleast 3 weeks of rest. The number of cycles administered is from about 1to about 12 cycles, more typically from about 2 to about 10 cycles, andmore typically from about 2 to about 8 cycles.

In other embodiments, courses of treatment are administered concurrentlyto a patient, i.e., individual doses of the second agent areadministered separately yet within a time interval such that thecompound provided herein can work together with the second active agent.In certain embodiments, one component can be administered once per weekin combination with the other components that can be administered onceevery two weeks or once every three weeks. In other words, the dosingregimens are carried out concurrently even if the therapeutics are notadministered simultaneously or during the same day.

The second agent can act additively or synergistically with the compoundprovided herein. In certain embodiments, the compound provided herein isadministered concurrently with one or more second agents in the samepharmaceutical composition. In another embodiment, a compound providedherein is administered concurrently with one or more second agents inseparate pharmaceutical compositions. In still another embodiment, acompound provided herein is administered prior to or subsequent toadministration of a second agent. Also contemplated are administrationof a compound provided herein and a second agent by the same ordifferent routes of administration, e.g., oral and parenteral. Incertain embodiments, when the compound provided herein is administeredconcurrently with a second agent that potentially produces adverse sideeffects including, but not limited to, toxicity, the second active agentcan advantageously be administered at a dose that falls below thethreshold that the adverse side effect is elicited.

Kits

Also provided are kits for use in methods of treatment of a condition,disease, or disorder by inhibiting MYST family of lysine acetyltransferases, including KAT6A and KAT6B. The kits can include a compoundor composition provided herein, a second agent or composition, andinstructions providing information to a health care provider regardingusage for treating a condition, disease, or disorder by inhibiting MYSTfamily of lysine acetyl transferases, including KAT6A and KAT6B.Instructions may be provided in printed form or in the form of anelectronic medium such as a floppy disc, CD, or DVD, or in the form of awebsite address where such instructions may be obtained. A unit dose ofa compound or composition provided herein, or a second agent orcomposition, can include a dosage such that when administered to asubject, a therapeutically or prophylactically effective plasma level ofthe compound or composition can be maintained in the subject for atleast 1 day. In some embodiments, a compound or composition can beincluded as a sterile aqueous pharmaceutical composition or dry powder(e.g., lyophilized) composition.

In some embodiments, suitable packaging is provided. As used herein,“packaging” includes a solid matrix or material customarily used in asystem and capable of holding within fixed limits a compound providedherein and/or a second agent suitable for administration to a subject.Such materials include glass and plastic (e.g., polyethylene,polypropylene, and polycarbonate) bottles, vials, paper, plastic, andplastic-foil laminated envelopes and the like. If e-beam sterilizationtechniques are employed, the packaging should have sufficiently lowdensity to permit sterilization of the contents.

Methods of Use

Inhibitors of post-translational lysine acetylation mediated by KATs ofthe MYST family are considered to be promising anti-neoplastic agentsand therefore may be useful therapeutic agents, e.g. for use in thetreatment of cancer. Such agents may also be useful as therapeuticagents for the treatment of cancers which exhibit overexpression of MYSTproteins.

Provided herein is a method for treating a condition, disease, ordisorder by inhibiting MYST family of lysine acetyl transferases,including KAT6A and KAT6B, in a subject, which comprises contacting thesubject with a therapeutically effective amount of a compound disclosedherein, e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (le),(If), (Ig), (Ih), (Ii), (Ij), (Ia-1), (Ib-1), (Ic-1), (Ic-2), (Id-1),(Ie-1), (If-1), or (Ig-1), Embodiments A, B and 1-72, including a singleenantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, a mixture of diastereomers, an individual stereoisomer, amixture of stereoisomers, an individual geometric isomer, a mixture ofgeometric isomers, or a tautomeric form thereof; or a pharmaceuticallyacceptable salt, solvate, prodrug, phosphate, or active metabolitethereof.

In certain embodiments, provided herein are methods for treating acondition, disease, or disorder by inhibiting MYST family of lysineacetyl transferases, including KAT6A and KAT6B, in a subject. In certainembodiments, the methods encompass the step of administering to thesubject in need thereof an amount of a compound effective for thetreatment of a condition, disease, or disorder by inhibiting MYST familyof lysine acetyl transferases, including KAT6A and KAT6B, in combinationwith a second agent. The compound can be any compound as describedherein, and the second agent can be any second agent described in theart or herein. In certain embodiments, the compound is in the form of apharmaceutical composition or dosage form, as described elsewhereherein.

Diseases which can be treated with the Compound according to any of theFormulas described herein, including Compounds in Embodiments A, B and1-72, include leukemia, acute lymphocytic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostatecancer, lung cancer, melanoma, breast cancer, breast ductal carcinoma,colon and rectal cancer, colon cancer, squamous cell carcinoma, gastriccancer, adrenocortical cancer, anal cancer, bladder cancer, bloodcancer, bone cancer, brain tumor, cancer of the female genital system,cancer of the male genital system (including testicular cancer andpenile cancer), central nervous system lymphoma, cervical cancer,childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer,endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer,gastrointestinal tract cancer, hairy cell leukemia, head and neckcancer, hepatocellular cancer, hypopharyngeal cancer, Kaposi's sarcoma,kidney cancer, laryngeal cancer, liver cancer, malignant fibroushistiocytoma, malignant thymoma, mesothelioma, multiple myeloma,myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,nervous system cancer, neuroblastoma, oral cavity cancer, oropharyngealcancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroidcancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm,primary CNS lymphoma, rectal cancer, respiratory system, retinoblastoma,salivary gland cancer, skin cancer, small intestine cancer, soft tissuesarcoma, stomach cancer, testicular cancer, thyroid cancer, urinarysystem cancer, uterine cancer, uterine sarcoma, vaginal cancer,endocrine, neoplasms of the central nervous system (CNS), primary CNSlymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitaryadenoma, vascular system, Waldenstrom's macroglobulinemia and/or Wilms'tumor.

Assay Methods

Compounds can be assayed for efficacy in treating a condition, disease,or disorder by inhibiting MYST family of lysine acetyl transferases,including KAT6A and KAT6B, according to any assay known to those ofskill in the art. Exemplary assay methods are provided elsewhere herein.

Second Therapeutic Agents

In certain embodiments, the compounds and compositions provided hereinare useful in methods of treatment of a condition, disease, or disorderby inhibiting MYST family of lysine acetyl transferases, including KAT6Aand KAT6B, that comprise further administration of a second agent. Thesecond agent can be any agent known to those of skill in the art to beeffective for the treatment of a condition, disease, or disorder byinhibiting MYST family of lysine acetyl transferases, including KAT6Aand KAT6B, including those currently approved by the United States Foodand Drug Administration, or other similar body of a country foreign tothe United States.

In some embodiments, the disease is cancer and the second agent is acancer treatment. In some embodiments, the disease is cancer and thesecond agent is the standard of care treatment for the particular cancerto be treated. In some embodiments, the disease is cancer and the secondagent is a chemotherapeutic agent. In some embodiments, the second agentis selected from an alkylating agent (e.g. cyclophosphamide,mechlorethamine, chlorambucil, melphalan, dacarbazine (DTIC), anitrosoureas, temozolomide (oral dacarbazine); an anthracycline (e.g.daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin,idarubicin, mitoxantrone, and valrubicin); a cytoskeletal disruptor (ataxane, e.g. paclitaxel, Albumin-bound paclitaxel and docetaxel);epothilone; an Histone Deacetylase inhibitor (e.g. vorinostat andromidepsin); an inhibitor of Topoisomerase I (e.g. irinotecan andtopotecan); an inhibitor of Topoisomerase II (e.g. etoposide,teniposide, and tafluposide); a kinase inhibitor (e.g. sorafenib,cobimetinib, cabozantanib, lapatinib, bortezomib, erlotinib, gefitinib,imatinib, vemurafenib, and vismodegib); a nucleotide analog andprecursor analog (e.g. azacitidine, azathioprine, capecitabine,cytarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea,mercaptopurine, methotrexate, and tioguanine); a peptide antibiotic(e.g. bleomycin and actinomycin); a platinum agent (e.g. carboplatin,cisplatin, and oxaliplatin); a retinoid (e.g. tretinoin, alitretinoin,and bexarotene); a vinca alkaloid or derivative (e.g. Capecitabine,vinblastine, vincristine, vindesine, and vinorelbine); eribulin;ixabepilone; radiation; bevacizumab; olaparib; an aromatase inhibitor(e.g. letrozole, anastrozole, and exemestane); rituximab; ibritumomab;prednisone; a kinase inhibitor e.g. sorafenib, cobimetinib,cabozantanib, lapatinib, bortezomib, erlotinib, gefitinib, imatinib,vemurafenib, and vismodegib; a CDK1, 4, and/or 6 inhibitor, such aspalbociclib, Kisqali or Verzenio; immunotherapy, such as a checkpointinhibitor (e.g. pembrolizumab, nivolumab and atezolizumab; andenzalutamide.

In some embodiments, the disease is cancer and the second agent is aCDK1, 4, and/or 6 inhibitor. In some embodiments, the disease is cancerand the second agent is palbociclib, ribociclib, or abemaciclib.

In some embodiments, the disease is cancer and the second agent isimmunotherapy, such as a checkpoint inhibitor (e.g. pembrolizumab,nivolumab and atezolizumab.

In some embodiments, the disease is breast cancer and the second agentis fulvestrant.

In some embodiments, the disease is breast cancer (e.g. post-menopausalbreast carcinoma) and the second agent is radiation, docetaxel,paclitaxel, platinum agents (cisplatin, carboplatin), vinorelbine,capecitabine, liposomal doxorubicin, gemcitabine, mitoxantrone,ixabepilone, albumin-bound paclitaxel, eribulin, trastuzumab,pertuzimab, ado-trastuzumab, lapatinib, bevacizumab, olaparib,radiation, an aromatase inhibitor (e.g. letrozole, anastrozole, andexemestane), or tamoxifen.

In some embodiments, the disease is liver cancer (e.g. hepatocellularcarcinoma, hepatocellular carcinoma not amenable to surgical orlocoregional therapy) and the second agent is sorafenib.

In some embodiments, the disease is prostate cancer and the second agentis radiation, abiraterone, or enzalutamide.

In some embodiments, the disease is pancreatic adenocarcinoma and thesecond agent is radiation.

In some embodiments, the disease is ovarian cancer and the second agentis bevacizumab, olaparib, radiation, an aromatase inhibitor (e.g.letrozole, anastrozole, and exemestane), or tamoxifen.

In some embodiments, the disease is B cell lymphoma and the second agentis rituximab, radiation, ibritumomab, cyclophosphamide, doxorubicin,vincristine, or prednisone.

In certain embodiments, a compound provided herein is administered incombination with one second agent. In further embodiments, a compoundprovided herein is administered in combination with two second agents.In still further embodiments, a compound provided herein is administeredin combination with two or more second agents.

As used herein, the term “in combination” includes the use of more thanone therapy (e.g., one or more prophylactic and/or therapeutic agents).The use of the term “in combination” does not restrict the order inwhich therapies (e.g., prophylactic and/or therapeutic agents) areadministered to a subject with a disorder. A first therapy (e.g., aprophylactic or therapeutic agent such as a compound provided herein)can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes,45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequentto (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or12 weeks after) the administration of a second therapy (e.g., aprophylactic or therapeutic agent) to a subject with a disorder.

As used herein, the term “synergistic” includes a combination of acompound provided herein and another therapy (e.g., a prophylactic ortherapeutic agent) which has been or is currently being used to prevent,manage or treat a disorder, which is more effective than the additiveeffects of the therapies. A synergistic effect of a combination oftherapies (e.g., a combination of prophylactic or therapeutic agents)permits the use of lower dosages of one or more of the therapies and/orless frequent administration of said therapies to a subject with adisorder. The ability to utilize lower dosages of a therapy (e.g., aprophylactic or therapeutic agent) and/or to administer said therapyless frequently reduces the toxicity associated with the administrationof said therapy to a subject without reducing the efficacy of saidtherapy in the prevention or treatment of a disorder). In addition, asynergistic effect can result in improved efficacy of agents in theprevention or treatment of a disorder. Finally, a synergistic effect ofa combination of therapies (e.g., a combination of prophylactic ortherapeutic agents) may avoid or reduce adverse or unwanted side effectsassociated with the use of either therapy alone.

The active compounds provided herein can be administered in combinationor alternation with another therapeutic agent, in particular an agenteffective in the treatment of a condition, disease, or disorder byinhibiting MYST family of lysine acetyl transferases, including KAT6Aand KAT6B. In combination therapy, effective dosages of two or moreagents are administered together, whereas in alternation orsequential-step therapy, an effective dosage of each agent isadministered serially or sequentially. The dosages given will depend onabsorption, inactivation and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition,disease, or disorder to be treated. It is to be further understood thatfor any particular subject, specific dosage regimens and schedulesshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions.

Preparation of Compounds

The compounds provided herein can be prepared, isolated or obtained byany method apparent to those of skill in the art. Compounds providedherein can be prepared according to the Exemplary Preparation Schemesprovided below. Reaction conditions, steps, and reactants not providedin the Exemplary Preparation Schemes would be apparent to, and known by,those skilled in the art.

Additional steps and reagents not provided in the Exemplary PreparationSchemes would be known to those of skill in the art. Exemplary methodsof preparation are described in detail in the Examples herein.

GENERAL SCHEME 1

General Scheme 1A describes the preparation of a Compound of Formula (I)where R² is ring (b); one X¹ is CR³, and the other two are CH; and allother groups are as defined in the Summary or in any embodimentsdescribed herein. General Scheme 1B describes the preparation of aCompound of Formula (I) where R² is ring (b); one X¹ is CR³, and theother two are CH; R³ is —(CH₂)Y; Y is

and all other groups are as defined in the Summary or in any embodimentsdescribed herein.

General Scheme 1 describes the preparation of a Compound of Formula (I)

Scheme (A) describes a way to prepare the appropriately substitutedbenzo[d]isoxazole compounds where in Step 1, a 2-fluorobenzonitrile canbe converted to a benzo[d]isoxazol-3-amine scaffold by reacting withN-hydroxyacetamide in presence of a base like potassium t-butoxide. InStep 2, the free amine is reacted with R¹S(O)₂Cl in presence of a basesuch as triethylamine, pyridine or sodium hydride.

Scheme (B) describes a synthesis of compounds where R³ is —(CH₂)Y and Yis an appropriately substituted 5-membered heteroaryl such as apyrazole. This synthesis can be extended to other heteroaryls, includingC-linked heteroaryls by those skilled in the art.

The synthesis of the benzo[d]isoxazole compounds can be started with anappropriately substituted 2-fluoro-4-(hydroxymethyl)benzonitrile. Thehydroxy group can be converted to a substituted pyrazole moiety byreacting with a compound of formula Ms-X (where Ms-X is

in presence of a base such as CsCO₃ as shown in Step 1 above. Thefluorobenzonitrile can be converted to the benzo[d]isoxazol-3-aminescaffold by its reaction with N-hydroxyacetamide in presence of a baselike potassium t-butoxide (Step 2 above). In the next step (Step 3), thefree amine is reacted with R¹S(O)₂Cl in presence of a base such astriethylamine, pyridine or sodium hydride. The final steps involvedeprotection of the amine (Step 4) followed by amide formation (eithervia a reaction with R^(3a)C(O)Cl, where R^(3a) is selected from groupa), or via activation of R^(3a)C(O)OH, where R^(3a) is selected fromgroup a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt orother agents known to those skilled in the art) or sulfonamide formationwith a sulfonyl chloride (R^(3a)S(O)₂Cl, where R^(3a) is selected fromgroup a)) in the presence of a base such as triethyl amine in Step 5.

GENERAL SCHEME 2

General Scheme 2 describes the preparation of a Compound of Formula (I)where R² is ring (c);

is

R³ is —(CH₂)Y and Y is pyrazolyl or pyridinyl, each of which issubstituted with R^(Y); and all other groups are as defined in theSummary or in any embodiments described herein.

The [1,2,4]triazolo[4,3-a]pyridine compounds can be prepared by startingwith an appropriately substituted methyl-2-chloroisonicotinate. InScheme (A) above, with a reducing agent like LiBH4, the ester can bereduced to an alcohol (Step 1 above). The hydroxy group can be convertedto a substituted pyrazole moiety by reacting with a1-(methylsulfonyl)-1H-pyrazole of formula X in presence of a base suchas CsCO₃ as shown in Step 2 above. The resulting 2-chloropyridine can beconverted to the corresponding 2-hydrazinopyridine by heating inpresence of hydrazine hydrate (Step 3). In Step 4, reaction withcyanogen bromide can lead to the assembly of the[1,2,4]triazolo[4,3-a]pyridin-3-amine scaffold. Reaction with R¹S(O)₂Clin the presence of a base such as triethyl amine, pyridine or sodiumhydride can lead to the N-linked pyrazole substituted compounds. Thefinal steps involve deprotection of the amine (Step 4) followed by amideformation (either via a reaction with R^(3a)C(O)Cl, where R^(3a) isselected from group a), or via activation of R^(3a)C(O)OH, where R^(3a)is selected from group a), using a coupling agent such as HATU, HBTU,T3P, EDCI/HOBt or other agents known to those skilled in the art) orsulfonamide formation with a sulfonyl chloride (R^(3a)S(O)₂Cl, whereR^(3a) is selected from group a)) in the presence of a base such astriethyl amine in Step 6.

For the C-linked heteroaryl substituted final compounds, a slightlyaltered Scheme (B) can be used. In this case, the main difference isthat the hydroxymethyl pyridine can be converted to a bromomethyl groupusing phosphorus tribromide (Step 2). Eventually, this bromomethyl groupcan be subjected to Negishi coupling conditions with a 2-bromoheteroaryl compound (2-bromopyridine in Scheme (B)), through the mediation ofzinc dust followed by a palladium catalyst such astetrakis(triphenylphosphine)palladium. Such a method can be applied toother heteroaryl analogs as well.

GENERAL SCHEME 3

General Scheme 3 describes the preparation of a Compound of Formula (I)where R² is ring (c);

is

R³ is —(CH₂)Y and Y is pyrazolyl substituted with R^(Y) and optionallysubstituted with R^(2e); and all other groups are as defined in theSummary or in any embodiments described herein.

The [1,2,3]triazolo[1,5-a]pyridine compounds can be synthesized using asubstituted 2-cyanopyridine compound. The introduction of the N-linkedpyrazole moiety (Steps 1 and 2) can use procedures described above forthe [1,2,4]triazolo[4,3-a]pyridine compounds. The assembly of the corescaffold is described in Steps 3 and 4 above. The 2-cyano pyridine canbe converted to a 1-amino 2-cyano pyridine by reacting with asulfonylated hydroxyl amine (Step 3), followed by cyclization in thepresence of hydroxylamine and acetic anhydride. In the final step (Step5), the free amine can be reacted with R¹S(O)₂Cl in presence of a basesuch as triethyl amine, pyridine or sodium hydride. In this Scheme,R^(Y) can be a group that harbors an amine with an appropriateprotecting group. After scaffold assembly in Step 5, the final steps caninvolve deprotection of the amine followed by amide formation (eithervia a reaction with R^(3a)C(O)Cl, where R^(3a) is selected from groupa), or via activation of R^(3a)C(O)OH, where R^(3a) is selected fromgroup a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt orother agents known to those skilled in the art) or sulfonamide formationwith a sulfonyl chloride (R^(3a)S(O)₂Cl, where R^(3a) is selected fromgroup a)) in the presence of a base such as triethyl amine.

GENERAL SCHEME 4

General Scheme 4 describes the preparation of a Compound of Formula (I)where R² is ring (a) and R³ is —(CH₂)Y; and all other groups are asdefined in the Summary or in any embodiments described herein.

The benzopyrazole compounds can be synthesized by using an appropriatelysubstituted 2-fluorobenzonitrile as starting material. Steps 1, 2 and 3can be done as described previously in General Schemes 2 and 3 above.The fluoro benzonitrile intermediate can be converted to the N-methylbenzopyrazole (Step 4, using methyl hydrazine) or unsubstitutedbenzopyrazole (Step 5, using hydrazine) as shown above. In Step 6, thefree amine can be reacted with R¹S(O)₂Cl in presence of a base such astriethyl amine, pyridine or sodium hydride. In this Scheme, Y can be aheteroaryl with a substituent R^(Y) that harbors an amine with anappropriate protecting group. After scaffold assembly in Step 6, thefinal steps can involve deprotection of the amine followed by amideformation (either via a reaction with R^(3a)C(O)Cl, where R^(3a) isselected from group a), or via activation of R^(3a)C(O)OH, where R^(3a)is selected from group a), using a coupling agent such as HATU, HBTU,T3P, EDCI/HOBt or other agents known to those skilled in the art) orsulfonamide formation with a sulfonyl chloride (R^(3a)S(O)₂Cl, whereR^(3a) is selected from group a)) in the presence of a base such astriethyl amine.

GENERAL SCHEME 5

General Scheme 5 describes the preparation of a Compound of Formula (I)where R² is ring (c);

is

R³ is —(CH₂)Y; and all other groups are as defined in the Summary or inany embodiments described herein.

By starting with an appropriately substituted 2-cyano-4-formyl pyridine.Step(s) 1 constitute reduction of the aldehyde with NaBH₄ to the alcoholfollowed by substitution with leaving group, such as methylsulfonyl or ahalide, and can be done as described previously in Steps 2 and 3 ofGeneral Scheme 4. Reduction in Step 2 can be accomplished by treatingthe picolinonitrile with LAH in THF. Treatment of the 2-aminomethylpyridine intermediate with cyanogen bromide in toluene (Step 3) canafford the imidazo[1,5-a]pyridin-3-amine intermediate which can beconverted to the desired Compound of Formula I with R¹S(O)₂Cl and a basesuch as pyridine, triethylamine or sodium hydride as shown in Step 2 anddescribed in General Scheme 1(A). In this Scheme, Y can be a heteroarylwith a substituent R^(Y) that harbors an amine with an appropriateprotecting group. After scaffold assembly in Step 4, the final steps caninvolve deprotection of the amine followed by amide formation (eithervia a reaction with R^(3a)C(O)Cl, where R^(3a) is selected from groupa), or via activation of R^(3a)C(O)OH, where R^(3a) is selected fromgroup a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt orother agents known to those skilled in the art) or sulfonamide formationwith a sulfonyl chloride (R^(3a)S(O)₂Cl, where R^(3a) is selected fromgroup a)) in the presence of a base such as triethyl amine.

GENERAL SCHEME 6

General Scheme 6 describes the preparation of a Compound of Formula (I)where R² is ring (c);

is

R³ is —(CH₂)Y; and all other groups are as defined in the Summary or inany embodiments described herein.

An appropriately substituted 2-cyano-5-formyl pyridine can be subjectedto steps 1 and 2 following methods described in Scheme 5 above. Steps 3and 4 involve N-formylation followed by refluxing in phosphorusoxychloride to construct the imidazo[1,5-a]pyridine ring. Nitration andreduction with the reagents in Step 5 can lead to the substitutedimidazo[1,5-a]pyridin-1-amine. The final sulfonamide products can resultby reacting this amine with R¹S(O)₂Cl and a base such as pyridine,triethylamine or sodium hydride as shown in Step 6 and described inGeneral Scheme 1. In this Scheme, Y can be a heteroaryl with asubstituent R^(Y) that harbors an amine with an appropriate protectinggroup. After scaffold assembly in Step 6, the final steps can involvedeprotection of the amine followed by amide formation (either via areaction with R^(3a)C(O)Cl, where R^(3a) is selected from group a), orvia activation of R^(3a)C(O)OH, where R^(3a) is selected from group a),using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt or otheragents known to those skilled in the art) or sulfonamide formation witha sulfonyl chloride (R^(3a)S(O)₂Cl, where R^(3a) is selected from groupa)) in the presence of a base such as triethyl amine.

GENERAL SCHEME 7

General Scheme 7 describes the preparation of a Compound of Formula (I)where R² is ring (d); X^(2a) is O; one X² is CR⁴ and the other X² areeach CH; and all other groups are as defined in the Summary or in anyembodiments described herein.

The synthesis of the benzofuran compounds can be started with anappropriately substituted 2-hydroxybenzaldehyde compound. Cyclization tothe benzofuran compound (Step 1) occurs by heating with ethylbromoacetate in presence of a base such as K2CO3. The resulting acid canbe converted to the corresponding primary amide (Step 2) using ammoniumchloride and an amide coupling agent such as HATU, HBTU, T3P, EDCI/HOBtor other agents known to those skilled in the art, in presence of abase. The synthesis of the acyl sulfonamide in Step 3 can beaccomplished by deprotonating the primary amide with a base like NaH andthen reacting with an appropriately substituted sulfonyl chloride. Step4 constitutes deprotection of the amine protecting group followed byStep 5 where the amine is coupled with an appropriately substituted acidusing a coupling agent such as HBTU or with an appropriately substitutedacid chloride or sulfonyl chloride in the presence of a base such astriethyl amine. In this Scheme, R⁴ can be a linker that harbors an aminewith an appropriate protecting group. After scaffold assembly in Step 3,the final steps can involve deprotection of the amine followed by amideformation (either via a reaction with R^(3a)C(O)Cl, where R^(3a) isselected from group a), or via activation of R^(3a)C(O)OH, where R^(3a)is selected from group a), using a coupling agent such as HATU, HBTU,T3P, EDCI/HOBt or other agents known to those skilled in the art) orsulfonamide formation with a sulfonyl chloride (R^(3a)S(O)₂Cl, whereR^(3a) is selected from group a)) in the presence of a base such astriethyl amine.

GENERAL SCHEME 8

General Scheme 8 describes the preparation of a Compound of Formula (I)where R² is ring (e) or ring (f); and all other groups are as defined inthe Summary or in any embodiments described herein.

The synthesis of the N′-benzoyl sulfonyl hydrazide compounds of Formula(I) can be started with a Suzuki coupling of an appropriatelysubstituted 2-bromoheteroaryl or a Chan-Lam coupling of an appropriatelysubstituted pyrazole (for example) with methyl or ethyl 3-carboxyphenylboronic acid/ester (Step 1). In Step 2, the ester can be reacted withhydrazine hydrate under heating to convert to the correspondinghydrazide. The hydrazide can be converted to the sulfonyl hydrazide byreacting with an appropriately substituted sulfonyl chloride in thepresence of a base like pyridine. In this general Scheme, R⁵ can be a 5-or 6-membered monocyclic heteroaryl substituted with Z and optionallysubstituted with R^(2e).

Z harbors an amine with an appropriate protecting group. After scaffoldassembly in Step 3, the final steps can involve deprotection of theamine followed by amide formation (either via a reaction withR^(3a)C(O)Cl, where R^(3a) is selected from group a), or via activationof R^(3a)C(O)OH, where R^(3a) is selected from group a), using acoupling agent such as HATU, HBTU, T3P, EDCI/HOBt or other agents knownto those skilled in the art) or sulfonamide formation with a sulfonylchloride (R^(3a)S(O)₂Cl, where R^(3a) is selected from group a)) in thepresence of a base such as triethyl amine.

GENERAL SCHEME 9

General Scheme 9 describes the preparation of a Compound of Formula (I)where R² is ring (g), where Q¹ and Q² are each N and Q³ is 0; or Q² andQ³ are each N and Q¹ is S or O; or Q¹ is CH, Q² is N, and Q³ is O.

Ring (g) can be assembled by reaction of an appropriately substitutedphenyl-heteroaryl amine with R¹S(O)₂Cl in presence of a base such astriethyl amine, pyridine or sodium hydride. In ring (g), R⁶ is amonocyclic heteroaryl substituted with Q and optionally substituted withR^(2e); or R⁶ is Q. Q initially harbors an amine with an appropriateprotecting group. After scaffold assembly in Step 1, the final steps caninvolve deprotection of the amine followed by amide formation (eithervia a reaction with R^(3a)C(O)Cl, where R^(3a) is selected from groupa), or via activation of R^(3a)C(O)OH, where R^(3a) is selected fromgroup a), using a coupling agent such as HATU, HBTU, T3P, EDCI/HOBt orother agents known to those skilled in the art) or sulfonamide formationwith a sulfonyl chloride (R^(3a)S(O)₂Cl, where R^(3a) is selected fromgroup a)) in the presence of a base such as triethyl amine.

The assembly of the key intermediate (phenyl-heteroaryl amine) shown inStep 1(A) can be done through various means, as known to persons skilledin the art. Some examples are drawn in the Scheme 9(B). In row (1), anappropriately substituted benzoic acid can be activated using a couplingagent such as HATU, HBTU, T3P, EDCI/HOBt or other agents known to thoseskilled in the art, then reacting with guanidine. The cyclization to theaminoheteroaryl intermediate can accomplished through the mediation ofiodobenzene diacetate. In row (2), an appropriately substitutedbenzaldehyde can be condensed with semicarbazide/thiosemicarbazide inthe presence, but not limited to NaOAc. The oxidative cyclization to thekey aminoheteroaryl intermediate can be accomplished in the presence ofiodine and a base such as K₂CO₃ or Cs₂CO₃. In another instance (Row 3),an appropriately substituted methylbenzoate ester can be converted tothe corresponding 3-oxo-3-phenylpropanenitrile using a base such as LDAand reacting with acetonitrile. Cyclization to the amino isoxazolecompound occurs in the presence of hydroxyl amine. Row 4 illustratesanother general method to assemble this key intermediate. A protected2-amino 5-bromo substituted heteroaryl compound can undergo Suzukicoupling (or other coupling conditions known to those skilled in theart) with an appropriately substituted phenyl boronic acid (or boronicester). Subsequent deprotection of the amine can afford the desired keyintermediate.

GENERAL SCHEME 10

General Scheme 10 describes the preparation of a Compound of Formula (I)where R² is ring (b); one X¹ is C(CH₂R^(2c)), and the other two X¹ areCR^(2e); and R^(2c) is pyrazol-1-yl substituted with two R^(2c1); andall other groups are as defined in the Summary or in any embodimentsdescribed herein.

The synthesis of the benzo[d]isoxazole compounds can be started with anappropriately substituted 2-fluoro-4-(hydroxymethyl)benzonitrile. Thehydroxy group can be converted to a substituted pyrazole moiety byreacting with a 1-(methylsulfonyl)-1H-pyrazole of formula X in presenceof a base such as CsCO₃ as shown in Step 1 above. The fluorobenzonitrilecan be converted to the benzo[d]isoxazol-3-amine scaffold by itsreaction with N-hydroxyacetamide in presence of a base like potassiumt-butoxide (Step 2 above). In the final step (Step 3), the free aminecan be reacted with R¹S(O)₂Cl in presence of a base such astriethylamine, pyridine or sodium hydride.

GENERAL SCHEME 11

General Scheme 11 describes the preparation of a Compound of Formula (I)where R² is ring (c);

is

one X¹ is C(CH₂R^(2c)) and the other two X¹ are CR^(2e); and R^(2c) ispyrazol-1-yl substituted with two R^(2c1); and all other groups are asdefined in the Summary or in any embodiments described herein.

The [1,2,4]triazolo[4,3-a]pyridine compounds can be prepared by startingwith an appropriately substituted methyl-2-chloroisonicotinate. InScheme (A) above, with a reducing agent like LiBH₄, the ester can bereduced to an alcohol (Step 1 above). The hydroxy group can be convertedto a substituted pyrazole moiety by reacting with a1-(methylsulfonyl)-1H-pyrazole of formula X in presence of a base suchas CsCO₃ as shown in Step 2 above. The resulting 2-chloropyridine can beconverted to the corresponding 2-hydrazinopyridine by heating inpresence of hydrazine hydrate (Step 3). In Step 4, reaction withcyanogen bromide can lead to the assembly of the[1,2,4]triazolo[4,3-a]pyridin-3-amine scaffold. Reaction with R¹S(O)₂Clin the presence of a base such as triethyl amine, pyridine or sodiumhydride can lead to the N-linked pyrazole substituted final compounds.

For the C-linked heteroaryl substituted final compounds, a slightlyaltered Scheme (B) can be used. In this case, the main difference isthat the hydroxymethyl pyridine can be converted to a bromomethyl groupusing phosphorus tribromide (Step 2). Eventually, this bromomethyl groupcan be subjected to Negishi coupling conditions through the mediation ofzinc dust followed by a palladium catalyst such astetrakis(triphenylphosphine)palladium. Such a method can be applied toother heteroaryl analogs as well.

GENERAL SCHEME 12

General Scheme 12 describes the preparation of a Compound of Formula (I)where R² is ring (c);

is

one X¹ is C(CH₂R^(2c)) and the other two X¹ are CR^(2e); and R^(2c) ispyrazol-1-yl substituted with two R^(2c1); and all other groups are asdefined in the Summary or in any embodiments described herein.

The [1,2,3]triazolo[1,5-a]pyridine compounds can be synthesized using asubstituted 2-cyanopyridine compound. The introduction of the N-linkedpyrazole moiety (Steps 1 and 2) can use procedures described above forthe [1,2,4]triazolo[4,3-a]pyridine compounds. The assembly of the corescaffold is described in Steps 3 and 4 above. The 2-cyano pyridine canbe converted to a 1-amino 2-cyano pyridine by reacting with asulfonylated hydroxyl amine (Step 3), followed by cyclization in thepresence of hydroxylamine and acetic anhydride. In the final step (Step5), the free amine can be reacted with R¹S(O)₂Cl in presence of a basesuch as triethyl amine, pyridine or sodium hydride.

GENERAL SCHEME 13

General Scheme 13 describes the preparation of a Compound of Formula (I)where R² is ring (a); one X¹ is C(CH₂R^(2c)), and the other two X¹ areCR^(2e); and R^(2c) is pyrazol-1-yl substituted with two R^(2c1); andall other groups are as defined in the Summary or in any embodimentsdescribed herein.

The benzopyrazole compounds can be synthesized by using an appropriatelysubstituted 2-fluorobenzonitrile as starting material. Steps 1, 2 and 3can be done as described previously in the synthesis of the[1,2,4]triazolo[4,3-a]pyridine compounds (General Schemes 2 and 3above). The fluoro benzonitrile intermediate can be converted to theN-methyl benzopyrazole (Step 4, using methyl hydrazine) or unsubstitutedbenzopyrazole (Step 5, using hydrazine) as shown above. In the finalstep (Step 6), the free amine can be reacted with R¹S(O)₂Cl in presenceof a base such as triethyl amine, pyridine or sodium hydride.

GENERAL SCHEME 14

General Scheme 14 describes the preparation of a Compound of Formula (I)where R² is ring (c);

is

and all other groups are as defined in the Summary or in any embodimentsdescribed herein, can be prepared as shown below:

By starting with an appropriately substituted 2-cyano-4-formyl pyridine.Step(s) 1 constitute reduction of the aldehyde with NaBH₄ to the alcoholfollowed by substitution with R^(2c)-LG, where R², is as defined in anyaspect or embodiment provided herein, and LG is a leaving group, such asmethylsulfonyl or a halide, and can be done as described previously inSteps 2 and 3 of General Scheme 13. Reduction in Step 2 can beaccomplished by treating the picolinonitrile with LAH in THF. Treatmentof the 2-aminomethyl pyridine intermediate with cyanogen bromide intoluene (Step 3) can afford the imidazo[1,5-a]pyridin-3-amineintermediate which can be converted to the desired Compound of FormulaII with R¹S(O)₂Cl and a base such as pyridine, triethylamine or sodiumhydride as shown in Step 4 and described in General Scheme 10.

GENERAL SCHEME 15

General Scheme 15 describes the preparation of a Compound of Formula (I)where R² is ring (c);

is

and all other groups are as defined in the Summary or in any embodimentsdescribed herein, can be prepared as shown below:

An appropriately substituted 2-cyano-5-formyl pyridine can be subjectedto steps 1 and 2 following methods described in Scheme A above. Steps 3and 4 involve N-formylation followed by refluxing in phosphorusoxychloride to construct the imidazo[1,5-a]pyridine ring. Nitration andreduction with the reagents in Step 5 can lead to the substitutedimidazo[1,5-a]pyridin-1-amine. The final sulfonamide products can resultby reacting this amine with R¹S(O)₂Cl and a base such as pyridine,triethylamine or sodium hydride as shown in Step 6 and described inGeneral Scheme 10.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); L (microliters); mM (millimolar); M (micromolar); Hz(Hertz); MHz (megahertz); mmol (millimoles); h, hr or hrs (hours); min(minutes); MS (mass spectrometry); ESI (electrospray ionization); rt(room temperature); Rf (retention factor); TLC (thin-layerchromatography); LCMS (liquid chromatography-mass spectrometry); HPLC(high performance liquid chromatography); AcOH (acetic acid); n-BuLi(n-Butyl lithium); ^(t)BuOK (potassium tert-butoxide); CDCl₃(Chloroform-d); CH₃CN (acetonitrile); Cs₂CO₃ (cesium carbonate); DMF(N,N-Dimethylformamide); DCM (dichloromethane); DEA (diethylamine);DIPEA (diisopropyl ethylamine); DMSO (dimethylsulfoxide); DMSO-d₆(dimethyl sulfoxide-d₆); EtOAc or EA (ethyl acetate); Et₃N(triethylamine); EtOH (ethanol); HCl (hydrochloric acid); H₂SO₄(sulphuric acid); K₂CO₃ (potassium carbonate); LiOH (lithium hydroxide);MsCl (methane sulphonyl chloride); Mel (methyl iodide); MeOH (Methanol);MeOH-d₄ (Methanol-d₄); NaBH₄ (sodium borohydride); NaH (sodium hydride);NaHCO₃ (sodium bicarbonate); NaNO₂ (sodium nitrite); NaOH (sodiumhydroxide); NaOMe (sodium methoxide); Na₂SO₄ (sodium sulphate);Pd(PPh₃)₄ (tetrakis(triphenylphosphine)palladium(0)); SO₂ (sulphurdioxide); SO₂Cl₂ (sulfuryl chloride); T3P (propanephosphonic acidanhydride); THF (tetrahydrofuran); TMEDA (1,2-bis(dimethylamino)ethane);Zn (zinc); ZnCN₂ (zinc cyanide).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCelsius). All reactions are conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

SYNTHETIC INTERMEDIATE EXAMPLES

Step 1: Synthesis of S-(cyclohexylmethyl) ethanethioate (2)

To a stirred solution of compound 1 (2 g, 11.3 mmol) in DMF (20 mL) wasadded potassium thioacetate (1.93 g, 17 mmol) in portion-wise manner atthe room temperature. The reaction mixture was stirred at 50° C. for 1h. The progress of the reaction was monitored by TLC. After completion,the reaction mixture was diluted with ice water and extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford thetitle compound 2 (1.8 g, 92.61%) as a dark brown liquid. TLC: Heptane(R_(f). 0.7) ¹H NMR (400 MHz, CDCl₃): δ 2.79 (d, J=6.8 Hz, 2H), 2.33 (s,3H), 1.79-1.61 (m, 5H), 1.49-1.38 (m, 1H), 1.27-1.12 (m, 3H), 1.05-0.89(m, 2H).

Step 2: Synthesis of cyclohexyl methane sulfonyl chloride (3)

To a stirred solution of N-chlorosuccinimide (2.7 g, 20.3 mmol) in 2NHCl (1.7 mL) at 0° C. was added a pre-dissolved solution of compound 2(1 g, 0.58 mmol) in acetonitrile (10 mL). The reaction mixture wasstirred at room temperature for 30 min. The progress of the reaction wasmonitored by TLC. After completion, the reaction mixture wasconcentrated in vacuo and the residue was extracted with diethyl ether.The organic layer was collected, washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by silica gel (100-200 mesh) column chromatography using agradient method of 0-5% EtOAc/Heptane to afford the title compound 3(0.81 g, 71%) as a yellow liquid. TLC: 10% EtOAc/Heptane (R_(f). 0.25)¹H NMR (400 MHz, CDCl₃): δ 3.63 (d, J=6.4 Hz, 2H), 2.24-2.18 (m, 1H),2.01-1.96 (m, 2H), 1.80-1.66 (m, 3H), 1.40-1.29 (m, 2H), 1.25-1.11 (m,3H).

To a stirred solution of 1,3-dimethoxybenzene 4 (2 g, 14.4 mmol) andTMEDA (2.4 mL, 15.9 mmol) in THF (20 mL) at 0° C. under Nitrogenatmosphere was added ^(n)BuLi [2.5 M solution in hexanes] (6.3 mL, 15.9mmol) in drop-wise manner while keeping the internal reactiontemperature below 5° C. The contents were stirred at the sametemperature for 30 min, then cooled to −78° C. and bubbled with SO₂ gasfor 30 min. The reaction mixture was then allowed to warm slowly to 10°C. and the resulting precipitate was collected by filtration and washedwith dry diethyl ether. The solid was suspended in hexane (20 ml),cooled to 0° C. and a solution of SO₂C₂ (2.2 mL, 28.8 mmol) in hexane(20 mL) was added drop wise manner while keeping the internaltemperature below 3° C. The reaction mixture was then stirred at 0° C.for 1 h and the solids were collected by filtration and washed with coldhexane. The solids were partitioned between diethyl ether and water, thelayers were separated; the aqueous layer was further extracted withdiethyl ether. The combined organic extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound 5 (1 g, 29.23%) as a white solid. TLC: 10% EtOAc/Heptane(R_(f). 0.3) ¹H NMR (400 MHz, DMSO-d₆): δ 7.27 (t, J=8.0 Hz, 1H), 6.64(d, J=8.8 Hz, 2H), 3.72 (s, 6H).

To a stirred solution of compound 6 (0.1 g, 0.5 mmol) in DMF (2 mL) at−40° C. was added NaHMDS (0.5 mL, 0.5 mmol) followed by methane sulfonylchloride (0.04 mL, 0.55 mmol) and the resulting reaction mixture wasallowed to stir at the room temperature for 3 h. After completion of thereaction (monitored by TLC), the reaction mixture was quenched withsaturated NH₄Cl solution and extracted with ethyl acetate. The organiclayer was collected, washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford the titlecompound 7 (0.06 g, 42.98%) as a white gummy solid. TLC: 50%EtOAc/Heptane (R_(f). 0.4). ¹H NMR (400 MHz, DMSO-d₆): δ 8.08 (s, 1H),7.84 (s, 1H), 7.29 (broad s, 1H), 4.02 (broad s, 2H), 3.50 (s, 3H), 1.39(s, 9H). LCMS Calculated for C₁₀H₁₇N₃O₄S: 275.32; Found: 299.90 (M+23).

Step 1: Synthesis of tert-butyl ((1H-pyrazol-3-yl)methyl)carbamate (9)

To a stirred solution of compound 8 (1 g, 10.30 mmol) in DCM (50 mL) at0° C. was added (Boc)₂O (2.12 mL, 9.27 mmol) and the reaction mixturewas allowed to stir at the room temperature for 3 h. After completion ofthe reaction (monitored by TLC), the reaction mixture was quenched withwater and extracted with DCM. The organic layer was collected, washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford the title compound 9 (1.7 g, 83.7%) as a white solid.TLC: 70% EtOAc/Heptane (R_(f). 0.3). LCMS Calculated for C₉H₁₅N₃O₂:197.24; Found: 198.2 (M+1).

Step 2: Synthesis of tert-butyl((1-(methylsulfonyl)-1H-pyrazol-3-yl)methyl)carbamate (10) andtert-butyl ((1-(methylsulfonyl)-1H-pyrazol-5-yl)methyl)carbamate (10A)

To a stirred solution of compound 9 (1.7 g, 8.62 mmol) in DMF (25 mL) at−40° C. was added NaHMDS (8.6 mL, 8.62 mmol) followed by methanesulfonyl chloride (0.72 mL, 9.40 mmol) and the resulting reactionmixture was allowed to stir at the room temperature for 3 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasquenched with saturated NH₄Cl solution and extracted with ethyl acetate.The organic layer was collected, washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound 10 (0.9 g, 38.1%) as a white gummy solid. TLC: 50%EtOAc/Heptane (R_(f). 0.4). ¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (d, J=2.4Hz, 1H), 7.41 (t, J=6.0 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.15 (d, J=6.4Hz, 2H), 3.50 (s, 3H), 1.40 (s, 9H). ¹H NMR indicates 10 as the majorisomer. LCMS Calculated for C₁₀H₁₇N₃O₄S: 275.32; Found: 273.95 (M−1) and10A is minor isomer and found to be less pure and was discarded.

To a stirred solution of compound 11 (2.0 g, 9.56 mmol) in DMF (20 mL)at 0° C. was added NaHMDS (9.5 mL, 9.56 mmol) followed by methanesulfonyl chloride (0.85 mL, 10.51 mmol) and the resulting reactionmixture was allowed to stir at −40° C. for 2 h. After completion of thereaction (monitored by TLC), the reaction mixture was concentrated underreduced pressure, water was added to the residue and extracted withethyl acetate. The organic layer was collected, washed with saturatedNaHCO₃ solution followed by brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound 12 (1.2g, 43.69%) as a pale yellow liquid. TLC: 50% EtOAc/Heptane (R_(f). 0.4).¹H NMR (400 MHz, DMSO-d₆): δ 8.00-8.10 (m, 1H), 4.50-4.52 (m, 2H),4.33-4.31 (m, 2H), 3.53 (s, 3H), 1.45 (s, 9H). VT NMR at 80° C.indicates a 1:1 mixture of rotamers.

Synthesis of Compounds of Formula (I) Synthetic Examples 1-3

(Note that only one regioisomer of compounds for 16, 17, 18, and 18a aredepicted in the above scheme and throughout examples 1-3; however, bothare present in the reaction mixtures.)

Synthesis of 2,6-difluoro-4-(hydroxymethyl)benzonitrile (14)

To a stirred solution of compound 13 (5 g, 29.00 mmol) in THF (50 mL) at0° C. was added NaBH₄ (1.6 g, 44.00 mmol) and the resulting reactionmixture was stirred at the same temperature for 2 h. After completion ofthe reaction (monitored by TLC), the reaction mixture was neutralizedwith 1N HCl and extracted with ethyl acetate. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound 14 (4.5g, 88.93%) as a yellow solid. TLC: 30% EtOAc/Heptane (R_(f). 0.35). ¹HNMR (400 MHz, DMSO-d₆): δ 7.35-7.32 (m, 2H), 5.69 (t, J=6.0 Hz, 1H),4.60 (d, J=6.0 Hz, 2H).

Synthesis of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (15)

To a stirred solution of compound 14 (4 g, 23.12 mmol) in MeOH (60 mL)at −40° C. was added NaOMe (5.1 g, 94.00 mmol) and the reaction mixturewas allowed to stir at the room temperature for 16 h. After completionof the reaction (monitored by TLC), the solvent was concentrated underhigh vacuum. Water was added to the residue and extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford thetitle compound 15 (3.5 g, 81.69%) as a yellow solid. TLC: 50%EtOAc/Heptane (R_(f). 0.25). ¹H NMR (400 MHz, CDCl₃): δ 6.81-6.78 (m,2H), 4.75 (s, 2H), 3.96 (s, 3H). OH proton not observed.

Synthesis of tert-butyl2-(4-cyano-3-fluoro-5-methoxybenzyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate(16)

To a stirred solution of compound 15 (1.0 g, 5.5 mmol) in acetonitrile(5 mL) was added Cs₂CO₃ (3.22 g, 9.90 mmol) followed by compound 12(1.74 g, 6.07 mmol) and the resulting reaction mixture was heated at 70°C. for 6 h. After completion of the reaction (monitored by TLC), thereaction mixture was cooled to room temperature, water was added andextracted with ethyl acetate. The organic layer was collected, washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound obtained was purified by silica gel(100-200 mesh) column chromatography using a gradient method of 0-50%EtOAc/Heptane to afford the title compound 16 (1.0 g, 48.65%, isolatedas inseparable regioisomeric mixture) as a yellow solid. TLC: 80%EtOAc/Heptane (R_(f). 0.45). LCMS Calculated for C₁₉H₂₁FN₄O₃: 372.40;Found: 373.85 (M+1). ¹H NMR is complicated and indicates an isomericmixture. This was taken on as a mixture for the synthesis of finalcompounds, where a single regioisomer is drawn.

Synthesis of tert-butyl2-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate(17)

To a stirred solution of compound 16 (0.50 g, 1.34 mmol) in DMF (7 mL)was added acetohydroxamic acid (0.31 g, 4.02 mmol) followed by ^(t)BuOK(0.45 g, 4.02 mmol) and the reaction mixture was allowed to stir at 65°C. for 16 h. After completion of the reaction (monitored by TLC), thereaction mixture was cooled to room temperature, quenched with ice waterand extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound obtained was purified by silica gel(100-200 mesh) column chromatography using a gradient method of 0-50%EtOAc/Heptane to afford the title compound 17 (0.20 g, 38.64%, isolatedas inseparable regioisomeric mixture) as an off-white solid. TLC: 70%EtOAc/Heptane (R_(f). 0.40). LCMS Calculated for C₁₉H₂₃N₅O₄: 385.42;Found: 386.00 (M+1). ¹H NMR is complicated and indicates a regioisomericmixture.

Synthesis of tert-butyl2-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate(18)

To a stirred solution of compound 17 (0.160 g, 0.42 mmol) in DCM (3 mL)was added Et₃N (0.15 mL, 1.14 mmol) followed bycyclohexylmethanesulfonyl chloride (3, 0.11 g, 0.58 mmol) at 0° C. andthe resulting reaction mixture was allowed to stir at room temperaturefor 2 h. After completion of the reaction (monitored by TLC), thereaction mixture was again cooled to room temperature, diluted with DCMand extracted. The organic layer was collected, washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by silica gel (100-200 mesh) column chromatographyusing a gradient method of 0-60% EtOAc/Heptane to afford the titlecompound 18 (0.18 g, 79.60%, isolated as inseparable regioisomericmixture) as an off-white solid. TLC: 80% EtOAc/Heptane (R_(f). 0.35).LCMS Calculated for C₂₆H₃₅N₅O₆S: 545.66; Found: 544.40 (M−1). ¹H NMR iscomplicated and indicates a regioisomeric mixture.

Synthesis of1-cyclohexyl-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide

To a stirred solution of compound 18 (180 mg, 0.33 mmol) in DCM (3 mL)was added TFA (0.13 mL, 1.73 mmol) at 0° C. and the reaction was allowedto stir at room temperature for 4 h. After completion of the reaction(monitored by TLC), reaction mixture was again cooled to roomtemperature, basified with sat. NaHCO₃ solution and extracted with DCM.The organic layer was collected, washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to obtain crude residuewhich was triturated with di-ethyl ether/pentane to afford the titlecompound (100 mg, 67.10%, isolated as inseparable regioisomeric mixture)as a white solid which was used in the next reaction without furtherpurification. LCMS Calculated for C₂₁H₂₇N₅O₄S: 445.54; Found: 446.50(M+1). ¹H NMR is complicated and indicates a regioisomeric mixture.

Synthetic Example 1 Synthesis of mixture ofN-(6-((5-acryloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamideand its regioisomer

To a stirred solution of 18a (0.050 g, 0.11 mmol) in DCM (3 mL) at 0° C.was added Et₃N (0.045 mL, 0.63 mmol) followed by acryloyl chloride (0.01g, 0.11 mmol). The reaction mixture was stirred at the room temperaturefor 2 h. After completion of the reaction (monitored by TLC), thereaction mixture was concentrated under reduced pressure and dilutedwith water and extracted with 5% MeOH/DCM. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byusing reverse phase HPLC to afford the title compound (7 mg, 9.9%,isolated as inseparable regioisomeric mixture) as an off-white solid.TLC: 5% MeOH/DCM (R_(f). 0.5). (See analytical data in Table 1).

Synthetic Example 2 Synthesis of a mixture of1-cyclohexyl-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)methanesulfonamideand its regioisomer

To a stirred solution of 18a (0.050 g, 0.11 mmol) in DMF (2 mL) at 0° C.was added DIPEA (0.06 mL, 0.39 mmol), followed by T₃P (0.06 mL, 0.22mmol). The reaction was allowed to stir at the room temperature for 20min. A pre-dissolved solution of propiolic acid (8 mg, 0.12 mmol) in DMF(0.5 mL) was added in a drop-wise manner and the reaction mixture wasstirred at room temperature for 2 h. After completion (monitored byTLC), the solvent was concentrated under high vacuum. The residue wasquenched with water and extracted with DCM. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byusing reverse phase HPLC to afford the title compound (6.1 mg, 11%,isolated as inseparable regioisomeric mixture) as an off-white solid.TLC: 5% MeOH/DCM (R_(f). 0.5). (See analytical data in Table 1).

Synthesis of 4-(dimethylamino)but-2-ynoic acid (20)

To a stirred solution of compound 19 (2.0 g, 0.24 mmol) in THF (20 mL)at −78° C. under inert atmosphere was added n-BuLi (15 mL, 0.24 mmol,1.6M in Hexane). The mixture was stirred at −78° C. for 1 h, then addedto another flask containing crushed CO₂ (11.5g, 0.241 mmol) and theresulting reaction mixture was allowed to stir at the same temperaturefor 30 min. The progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was poured in to ice water and washedwith ethyl acetate. The aqueous layer was collected and concentratedunder reduced pressure to afford the residue, which was diluted withMeOH and filtered. The filtrate was concentrated under reduced pressureto get the title compound 20 (1.4 g, 45.74%) as a pale brown solid. TLC:10% MeOH/DCM (Rf 0.3). ¹H NMR (400 MHz, DMSO-d₆): δ 3.15 (s, 2H), 2.14(s, 6H). LCMS Calculated for C₆H₉NO₂: 127.14; Found: 128.2 (M+1).

Synthetic Example 3 Synthesis of1-cyclohexyl-N-(6-((5-(4-(dimethylamino)but-2-ynoyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide

To a stirred solution of compound 18a (70 mg, 0.16 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.09 mL, 0.51 mmol), followed by compound 20(18 mg, 0.14 mmol). The resultant mixture was allowed to stir at 0° C.for 5 min. After that, T₃P (0.06 mL, 0.19 mmol) was added and thereaction was allowed to stir at the room temperature for 16 h. Aftercompletion (monitored by TLC), the reaction was quenched with water andextracted with ethyl acetate. The organic layer was collected, washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by using prep. HPLC to affordthe title compounds as a mixture of regioisomers (7 mg, 8%) as anoff-white solid. TLC: 10% MeOH/DCM (R_(f). 0.5). (See analytical datafor Table 1).

Synthetic Examples 4-6

Synthesis of tert-butyl((1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazol-4-yl)methyl)carbamate(21)

To a stirred solution of compound 15 (0.5 g, 2.76 mmol) in acetonitrile(10 mL) at the room temperature was added Cs₂CO₃ (2.7 g, 8.28 mmol)followed by compound 7 (1.13 g, 4.14 mmol) and the resulting reactionmixture was heated at 70° C. for 4 h. After completion of the reaction(monitored by TLC), the reaction mixture was cooled to room temperature,water added and extracted with ethyl acetate. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byCombi-flash chromatography using a gradient method of 40-70%EtOAc/Heptane to afford the title compound 21 (0.400 g, 40.22%) as abrown semi-solid. TLC: 80% EtOAc/Heptane (R_(f). 0.45). ¹H NMR (400 MHz,DMSO-d₆): δ 7.72 (s, 1H), 7.39 (s, 1H), 7.18-7.12 (m, 1H), 7.00 (s, 1H),6.69 (d, J=9.6 Hz, 1H), 5.37 (s, 2H), 3.96 (d, J=5.6 Hz, 2H), 3.91 (s,3H), 1.37 (s, 9H). LCMS Calculated for C₁₈H₂₁FN₄O₃: 360.39; Found:361.00 (M+1).

Synthesis of tert-butyl((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(22)

To a stirred solution of compound 21 (0.2 g, 0.55 mmol) in a 6:1 mixtureof DMF: H₂O (7 mL) at the room temperature was added acetohydroxamicacid (0.112 g, 1.50 mmol) followed by K₂CO₃ (0.414 g, 3.0 mmol). Thereaction mixture was allowed to stir at 60° C. for 16 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wascooled to room temperature, ice water added and extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by Combi flash chromatography using a gradientmethod of 40-60% EtOAc/Heptane to afford the title compound 22 (0.1 g,48.25%) as a brown semi-solid. TLC: 80% EtOAc/Heptane (R_(f). 0.40). ¹HNMR (400 MHz, DMSO-d₆): δ 7.67 (s, 1H), 7.35 (s, 1H), 7.18-7.12 (m, 1H),6.69 (s, 1H), 6.63 (s, 1H), 5.93 (s, 2H), 5.34 (s, 2H), 3.95 (d, J=6.0Hz, 2H), 3.86 (s, 3H), 1.36 (s, 9H). LCMS Calculated for C₁₈H₂₃N₅O₄:373.41; Found: 374.05 (M+1).

Synthesis of tert-butyl((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(23)

To a stirred solution of compound 22 (0.1 g, 0.26 mmol) in DCM (3 mL) at0° C. was added Et₃N (0.11 mL, 0.80 mmol) followed bycyclohexylmethanesulfonyl chloride (3, 0.057 g, 0.29 mmol) and thereaction was allowed to stir at the room temperature for 2 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasdiluted with DCM, water added and extracted. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byCombi flash column chromatography using a gradient method of 40-60%EtOAc/Heptane to afford the title compound 23 (0.070 g, 48.98%) as anoff-white solid. TLC: 80% EtOAc/Heptane (R_(f). 0.35). LCMS Calculatedfor C₂₅H₃₅N₅O₆S: 533.64; Found: 532.43 (M−1).

Synthesis ofN-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide

To a stirred solution of compound 23 (70 mg, 0.13 mmol) in DCM (2 mL) at0° C., TFA (0.1 mL, 1.31 mmol) was added, and the reaction was allowedto stir at the room temperature for 2 h. After completion of thereaction (monitored by TLC), it was concentrated under reduced pressureand the crude compound was purified by reverse phase HPLC to afford thetitle compound (4 mg, 7%) as an off-white solid. TLC: 5% MeOH/DCM(R_(f). 0.5). ¹H NMR (400 MHz, DMSO-d₆): δ 10.41 (broad s, 1H), 7.95(broad s, 2H), 7.91 (s, 1H), 7.58 (s, 1H), 6.92 (s, 1H), 6.83 (s, 1H),5.48 (s, 2H), 3.91 (merged s, 5H), 3.37 (merged d, J=5.6 Hz, 2H),2.04-1.91 (m, 1H), 1.86 (d, J=12.4 Hz, 2H), 1.61 (d, J=12.4 Hz, 2H),1.59-1.51 (m, 1H), 1.29-1.04 (m, 5H); LCMS Calculated for C₂₀H₂₇N₅O₄S:433.53; Found: 434.15 (M+1).

Synthetic Example 4 Synthesis ofN-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)acrylamide

To a stirred solution of compound 23a (60 mg, 0.13 mmol) in DCM (5 mL)at 0° C. was added Et₃N (0.09 mL, 0.65 mmol) followed by acryloylchloride (0.008 mL, 0.11 mmol) and the reaction was allowed to stir atthe same temperature for 20 min. After completion of the reaction(monitored by TLC), the reaction mixture was concentrated under reducedpressure, water added and extracted with 5% MeOH/DCM. The organic layerwas collected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byprep HPLC to afford the title compound (2.5 mg, 7.9%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 5 Synthesis ofN-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide

To a stirred solution of compound 23a (60 mg, 0.13 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.07 mL, 0.41 mmol), followed by T₃P (0.08 mL,0.27 mmol). The reaction was allowed to stir at the room temperature for20 min. After that, a pre-dissolved solution of propionic acid (11 mg,0.16 mmol) in DMF (0.5 mL) was added in drop-wise manner and thereaction was allowed to stir at the room temperature for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by using prep. HPLC toafford the title compound (6.5 mg, 10%) as an off-white solid. TLC: 100%EtOAc (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 6 Synthesis ofN-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)ethenesulfonamide

To a stirred solution of compound 23a (70 mg, 0.16 mmol) in THF (1 mL)was added NaH [60% dispersion in mineral oil] (12.8 mg, 0.32 mmol) at 0°C. followed by ethenesulfonyl chloride (22 mg, 0.17 mmol) and theresulting reaction mixture was allowed to stir at room temperature for 2h. After completion of the reaction (monitored by TLC), diluted withethyl acetate and extracted. The organic layer was collected, washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by using prep HPLC to affordthe title compound (3.5 mg, 4.0%) as an off-white solid. TLC: 80%EtOAc/Heptane (R_(f). 0.35). (See Table 1 for analytical data).

Synthetic Examples 7-9

Note that for the final compounds (Syn Ex. 7-9), the other regioisomerwas removed by purification and the isomer as drawn was obtained.

Synthesis of tert-butyl((1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazol-3-yl)methyl)carbamate(24 and its regioisomer)

To a stirred solution of compound 15 (0.2 g, 1.10 mmol) in acetonitrile(5 mL) at the room temperature was added Cs₂CO₃ (1.07 g, 3.30 mmol)followed by compound 10 (0.440 g, 1.60 mmol) and the resulting reactionmixture was heated at 70° C. for 6 h. After completion of the reaction(monitored by TLC), the mixture was cooled to room temperature, wateradded and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by Combi-flashchromatography using a gradient method of 40-70% EtOAc/Heptane to affordthe title compound 24 (0.180 g, 45.4%, isolated as inseparable mixture)as a brown semi-solid. TLC: 80% EtOAc/Heptane (R_(f). 0.45). ¹H NMR (400MHz, DMSO-d₆): δ 7.78 (s, 1H), 7.24-7.18 (m, 1H), 6.97 (s, 1H), 6.71 (d,J=9.6 Hz, 1H), 6.15 (d, J=2.0 Hz, 1H), 5.35 (s, 2H), 4.05 (d, J=5.6 Hz,2H), 3.91 (s, 3H), 1.37 (s, 9H). ¹H NMR indicates presence of minorregioisomer as well; LCMS Calculated for C₁₈H₂₁FN₄O₃: 360.39; Found:359.0 (M−1).

Synthesis of tert-butyl((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)carbamate(25 and its regioisomer)

To a stirred solution of compound 24 (0.18 g, 0.5 mmol) in a 6:1 mixtureof DMF: H₂O (7 mL) at room temperature was added N-hydroxyacetamide(0.112 g, 1.50 mmol) followed by K₂CO₃ (0.414 g, 3.0 mmol). The reactionmixture was allowed to stir at 60° C. for 16 h. After completion of thereaction (monitored by TLC), the reaction mixture was cooled to roomtemperature, ice water added and extracted with ethyl acetate. Theorganic layer was collected, washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by Combi flash chromatography using a gradient method of 40-60%EtOAc/Heptane to afford the title compound 25 (0.130 g, 69.7%, isolatedas inseparable mixture) as a brown semi-solid. TLC: 80% EtOAc/Heptane(R_(f). 0.40). ¹H NMR (400 MHz, DMSO-d₆): δ 7.78 (broad s, 1H),7.24-7.18 (m, 1H), 6.97 (s, 1H), 6.71 (d, J=10 Hz, 1H), 6.16 (s, 1H),5.35 (s, 2H), 4.05 (d, J=5.6 Hz, 2H), 3.94 (s, 3H), 1.37 (s, 9H). ¹H NMRindicates presence of minor regioisomer as well and NH₂ protons notobserved; LCMS Calculated for C₁₈H₂₃N₅O₄: 373.41; Found: 374.02 (M+1).

Synthesis of tert-butyl((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)carbamate(26 and its regioisomer)

To a stirred solution of compound 25 (0.130 g, 0.34 mmol) in DCM (3 mL)at 0° C. was added Et₃N (0.14 mL, 1.00 mmol) followed bycyclohexylmethanesulfonyl chloride (3, 0.081 g, 0.41 mmol) and thereaction was allowed to stir at the room temperature for 2 h. Aftercompletion of the reaction (monitored by TLC), the mixture was dilutedwith DCM, water added and extracted. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by Combi flash columnchromatography using a gradient method of 40-60% EtOAc/Heptane to affordthe title compound 26 (0.065 g, 34.99%, isolated as inseparable mixture)as a brown gummy solid. TLC: 80% EtOAc/Heptane (R_(f). 0.35). LCMSCalculated for C₂₅H₃₅N₅O₆S: 533.64; Found: 532.03 (M−1). ¹H NMR iscomplicated and indicates presence of minor regioisomer as a mixturewith the desired product.

Synthesis ofN-(6-((3-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide

To a stirred solution of compound 26 (65 mg, 0.12 mmol) in DCM (2 mL) at0° C., TFA (0.1 mL, 1.2 mmol) was added and the reaction was allowed tostir at the room temperature for 2 h. After completion of the reaction(monitored by TLC), it was concentrated under reduced pressure and thecrude compound was purified by reverse phase HPLC to afford the titlecompound (6 mg, 11.36%) as an off-white solid. TLC: 5% MeOH/DCM (R_(f).0.5). ¹H NMR (400 MHz, DMSO-d₆): δ 8.36 (broad s, 2H), 7.92 (d, J=2.0Hz, 1H), 6.66 (s, 1H), 6.54 (s, 1H), 6.37 (d, J=2.4 Hz, 1H), 5.37 (s,2H), 4.01 (s, 2H), 3.79 (s, 3H), 2.94 (d, J=6.0 Hz, 2H), 1.86 (d, J=12.4Hz, 2H), 1.79-1.76 (m, 1H), 1.61-1.53 (m, 3H), 1.24-1.05 (m, 3H), 0.94(q, J=11.2 Hz, 2H). LCMS Calculated for C₂₀H₂₇N₅O₄S: 433.53; Found:434.55 (M+1).

Synthetic Example 7 Synthesis of mixture ofN-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)acrylamideand its regioisomer

To a stirred solution of 26a (60 mg, 0.13 mmol) in DCM (5 mL) at 0° C.,was added Et₃N (0.09 mL, 0.65 mmol) followed by acryloyl chloride (0.008mL, 0.11 mmol) and the reaction was allowed to stir at the sametemperature for 20 min. After completion of the reaction (monitored byTLC), reaction mixture was concentrated under reduced pressure, addedwater and extracted with 5% MeOH/DCM. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by prep HPLC to affordthe title compound (5 mg, 7.4%, isolated as inseparable regioisomericmixture, ˜75% regioisomer as drawn) as an off-white solid. TLC: 5%MeOH/DCM (R_(f). 0.5). (See analytical data in Table 1).

Synthetic Example 8 Synthesis ofN-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)propiolamide

To a stirred solution of compound 26a (80 mg, 0.18 mmol) in DMF (2.5 mL)at 0° C. was added DIPEA (0.12 mL, 0.72 mmol), followed by T₃P (0.17 mL,0.27 mmol). The reaction was allowed to stir at the room temperature for20 min. After that, a pre-dissolved solution of propiolic acid (12 mg,0.18 mmol) in DMF (0.5 mL) was added in drop-wise manner and thereaction was allowed to stir at the room temperature for 16 h. Aftercompletion (monitored by TLC), solvent was concentrated under highvacuum. The residue was quenched with water and extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford crudecompound which was purified by using prep-HPLC to obtain inseparablemixture of isomers. The isomers were further separated by using ChiralHPLC (Method: Chiral-Met-B 30%_1.0 ml·Icm; Mobile phase: A; 0.1% DEA inn-Hexane; B; DCM:MeOH (50:50) A:B, 70:30; Injection volume: 10 μL; Flowrate: 1.0 mL/min; Column: CHIRAL PAK IG (250*4.6 mm, 5 μm); Duration upto 25 min.) to afford the title compound (27 mg, 31%) as a white solid.TLC: 100% EtOAc (R_(f). 0.5). (See Table 1 for analytical data). Minorisomer was not isolated in enough quantity due to merged impurities.

Synthetic Example 9 Synthesis ofN-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)propionamide

To a stirred solution of compound 26a (80 mg, 0.18 mmol) in DMF (2.5 mL)at 0° C. was added DIPEA (0.12 mL, 0.72 mmol), followed by T₃P (0.17 mL,0.27 mmol). The reaction was allowed to stir at the room temperature for20 min. After that, a pre-dissolved solution of propionic acid (13 mg,0.18 mmol) in DMF (0.5 mL) was added in drop-wise manner and thereaction was allowed to stir at the room temperature for 16 h. Aftercompletion (monitored by TLC), solvent was concentrated under highvacuum. The residue was quenched with water and extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford crudecompound which was purified by using prep-HPLC to obtain inseparablemixture of isomers. The isomers were further separated by using ChiralHPLC (Method: Chiral-Met-B 30% 1.0 ml·Icm; Mobile phase: A; 0.1% DEA inn-Hexane; B; DCM:MEOH (50:50) A:B, 70:30; Injection volume: 5 μL; Flowrate: 1.0 mL/min; Column: CHIRAL PAK IG (250*4.6 mm, 5 μm); Duration upto 25 min.) to afford the title compound (18 mg, 20%) as an off-whitesolid. TLC: 100% EtOAc (R_(f). 0.5). (See Table 1 for analytical data).Minor isomer was not isolated in enough quantity due to mergedimpurities.

Synthetic Examples 10-11

Synthesis of 6-bromobenzofuran-2-carboxylic acid (28)

To a stirred solution of compound 27 (10 g, 49.75 mmol) in DMF (100 mL)was added K₂CO₃ (20.6 g, 149.250 mmol) followed by ethyl 2-bromoacetate(11 mL, 99.50 mmol). The reaction mixture was allowed to stir at 160° C.for 16 h. After completion of the reaction (monitored by TLC), thereaction mixture was cooled to room temperature, acidified with 1N HCl(up to pH˜4-5) and extracted with ethyl acetate. The combined organiclayer was washed with water, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford the title compound 28 (5.2g, 43.33%) as a brown solid. This compound was used in the next stepwithout further purification. TLC: 80% EtOAc/heptane (R_(f). 0.5). ¹HNMR (400 MHz, DMSO-d₆): δ 13.5 (broad s, 1H), 8.05 (s, 1H), 7.95 (s,1H), 7.74 (d, J 8.8 Hz, 1H), 7.53 (dd, J=8.4, 1.2 Hz, 1H). LCMScalculated for C₉H₅BrO₃: 241.04; Found: 239.12 (M−2).

Synthesis of 6-bromobenzofuran-2-carboxamide (29)

To a stirred solution of compound 28 (1.5 g, 6.22 mmol) in DMF (15 mL)was added DIPEA (3.25 mL, 18.66 mmol) followed by HBTU (2.83 g, 7.46mmol) and NH₄Cl (1 g, 18.66 mmol). The reaction was stirred at the roomtemperature for 4 h. The progress of the reaction was monitored by TLC.After completion, water was added and extracted with ethyl acetate. Thecombined organic layer was washed with water, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to afford thetitle compound 29 (0.654 g, 43.78%) as a brown solid. This compound wasused in the next step without further purification. TLC: 80%EtOAc/heptane (R_(f). 0.6); ¹H NMR (400 MHz, DMSO-d₆): 8.15 (broad s,1H), 7.93 (s, 1H), 7.73 (d, J 8.4 Hz, 2H), 7.56 (s, 1H), 7.50 (dd,J=8.8, 1.6 Hz, 1H). LCMS Calculated for C₉H₆BrNO₂: 240.06; Found: 241.75(M+1).

Synthesis of6-bromo-N-((2-fluorophenyl)sulfonyl)benzofuran-2-carboxamide (30)

To a stirred solution of compound 29 (1.5 g, 6.30 mmol) in THF (20 mL)at 0° C. was added NaH [60% dispersion in mineral oil] (0.378 g, 9.45mmol) and the contents were stirred for 15 min. 2-Fluorobenzenesulfonylchloride (1.34 g, 6.93 mmol) was added and the reaction was allowed tostir at the room temperature for 4 h. After completion of the reaction(monitored by TLC), the reaction mixture was cooled to 0° C., quenchedwith ice water and extracted with ethyl acetate. The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by silica gel [100-200mesh] column chromatography to afford the title compound 30 (2.01 g,80.72%) as a white solid. TLC: 5% MeOH/DCM (R_(f). 0.2); ¹H NMR (400MHz, DMSO-d₆): δ 7.89 (s, 1H), 7.83 (t, J=8.0 Hz, 1H), 7.63 (d, J=8.4Hz, 1H), 7.46 (q, J=5.2 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.27-7.11 (m,3H). NH proton not observed; LCMS Calculated for C₁₅H₉BrFNO₄S: 398.20;Found: 400.15 (M+2).

Synthesis of 6-cyano-N-((2-fluorophenyl)sulfonyl)benzofuran-2-carboxamide (31)

To an argon purged solution of 30 (200 mg, 50 mmol) in DMF (5 mL) wasadded Zn(CN)₂ (73 mg, 0.63 mmol) followed by Zn dust (32 mg, 50 mmol)and purged again with argon for 15 min. Pd₂(dba)₃ (23 mg, 2.5 mmol) anddppf (37 mg, 5 mmol) were added to the resulting mixture. The reactionwas allowed to stir at 130° C. for 16 h. The progress of the reactionwas monitored by TLC. After completion, the reaction mixture wasfiltered through a pad of Celite which was washed with ethyl acetate.The filtrate was concentrated under reduced pressure. The crude compoundwas purified by prep-HPLC to afford the title compound 31 (0.348 g,80.18%) as an off-white solid. TLC: 5% MeOH/DCM (R_(f). 0.4); ¹H NMR(400 MHz, DMSO-d₆): δ 8.34 (s, 1H), 8.05-7.96 (m, 3H), 7.78-7.72 (m,2H), 7.48-7.41 (m, 2H). NH proton not observed; LCMS Calculated forC₁₆H₉FN₂O₄S: 344.32; Found: 345.05 (M+1).

Synthesis of6-(aminomethyl)-N-((2-fluorophenyl)sulfonyl)benzofuran-2-carboxamide(32)

An autoclave was charged with a solution of 31 (400 mg 1.16 mmol) inMeOH (10 mL) and the mixture was purged with nitrogen for 5 min. Apre-dissolved solution of Raney Ni (w/w of SM) in 7N NH₃/MeOH (5 mL) wasadded under nitrogen atmosphere. The reaction mixture was then purgedwith hydrogen and was allowed to stir under hydrogen atmosphere (100psi) at the room temperature for 4 h. The progress of the reaction wasmonitored by TLC. After completion, the reaction mixture was filteredthrough a pad of Celite which was washed with MeOH. The filtrate wasconcentrated under reduced pressure to dryness. The crude product waspurified by Combi flash chromatography (using a gradient method of 5%MeOH/DCM) to afford the desired title compound 32 (0.314 g, 78.5%) as ayellow solid. TLC: 5% MeOH/DCM (R_(f). 0.5); ¹H NMR (400 MHz, DMSO-d₆):δ 8.14 (broad s, 3H), 7.84 (t, J=7.2 Hz, 1H), 7.73 (s, 1H), 7.70 (d,J=2.8 Hz, 1H), 7.51-7.42 (m, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.27-7.14 (m,3H), 4.16 (d, J=3.6 Hz, 2H). LCMS Calculated for C₁₆H₁₃FN₂O₄S: 348.35;Found: 347.10 (M−1).

Synthetic Example 10 Synthesis of6-(acrylamidomethyl)-N-((2-fluorophenyl)sulfonyl)benzofuran-2-carboxamide

To a stirred solution of 32 (100 mg, 0.28 mmol) in DCM (5 mL) at 0° C.was added Et₃N (0.12 mL, 0.84 mmol), followed by acryloyl chloride (22.6mg, 0.28 mmol) and the reaction was allowed to stir at the roomtemperature for 2 h. After completion of the reaction (monitored byTLC), the reaction mixture was concentrated under reduced pressure,water added and extracted with 5% MeOH/DCM. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byusing reverse phase HPLC to afford the title compound (5 mg, 4.3%) as anoff-white solid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See analytical data inTable 1).

Synthetic Example 11 Synthesis ofN-((2-fluorophenyl)sulfonyl)-6-(propiolamidomethyl)benzofuran-2-carboxamide

To a stirred solution of 32 (150 mg, 0.43 mmol) in DMF (2 mL) at 0° C.was added DIPEA (0.22 mL, 1.29 mmol), followed by T₃P (205 μL, 0.64mmol). The reaction was allowed to stir at the room temperature for 20min. After that, a pre-dissolved solution of propiolic acid (30 mg, 0.43mmol) in DMF (0.5 mL) was added in a drop-wise manner and the reactionwas allowed to stir at the room temperature for 2 h. After completion(monitored by TLC), the solvent was concentrated under high vacuum. Theresidue was quenched with water and extracted with DCM. The organiclayer was collected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byusing reverse phase HPLC to afford the title compound (7 mg, 4%) as anoff-white solid. TLC: 10% MeOH/DCM (R_(f). 0.5). (See analytical data inTable 1).

Synthetic Examples 12-13

Synthesis of tert-butyl ((2-bromopyridin-4-yl)methyl)carbamate (34)

To a stirred solution of compound 33 (2 g, 10.92 mmol) in MeOH (30 mL)at 0° C. was added (Boc)²O (2.5 mL, 10.92 mmol) followed by NiCl₂·6H₂O(0.490 g, 2.06 mmol). After few minutes of stirring, the resultingmixture at the same temperature, was added NaBH₄ (1.24 g, 32.70 mmol)and the reaction was allowed to warm to room temperature and stirred for16 h. After completion of the reaction (monitored by TLC), water wasadded to the reaction mixture and extracted with ethyl acetate. Thecombined organic layer was collected, washed with saturated NaHCO₃solution, brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by combi flashchromatography (using a gradient method of 0-15% EtOAc/Heptane) toafford the title compound 34 (1.0 g, 32.0%) as a yellow solid. TLC: 30%EtOAc/Heptane (R_(f). 0.35); ¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (d, J=5.2Hz, 1H), 7.52 (t, J=5.6 Hz, 1H), 7.44 (s, 1H), 7.27 (d, J=4.8 Hz, 1H),4.14 (d, J=6.0 Hz, 2H), 1.34 (s, 9H); LCMS Calculated for C₁₁H₁₅BrN₂O₂:287.16; Found: 286.89 (M−1).

Synthesis of methyl3-(4-(((tert-butoxycarbonyl)amino)methyl)pyridin-2-yl)-5-methylbenzoate(35)

To a stirred solution of compound 34 (1.73 g, 6.03 mmol) in a 2:2:1mixture of Toluene: H₂O: EtOH (37 mL), was added K₂CO₃ (2.89 g, 20.90mmol) followed by Pd(PPh₃)₄ (0.231 g, 0.2 mmol) and methyl3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.2 g,4.19 mmol). The resulting reaction mixture was stirred at 80° C. for 12h. After completion (monitored by TLC), the reaction mixture was cooledto room temperature, water added and extracted with ethyl acetate. Theorganic layer was collected, washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by combi flash chromatography (using a gradient method of 0-50%EtOAc/Heptane) to afford the title compound 35 (0.9 g, 60.46%) as anoff-white solid. TLC: 80% EtOAc/Heptane (R_(f). 0.25). ¹H NMR (400 MHz,DMSO-d₆): δ 8.61 (d, J=4.4 Hz, 1H), 8.44 (s, 1H), 8.15 (s, 1H), 7.85 (s,2H), 7.59-7.54 (m, 1H), 7.24 (d, J=3.6 Hz, 1H), 4.24 (d, J=6.0 Hz, 2H),3.89 (s, 3H), 2.46 (s, 3H), 1.42 (s, 9H); LCMS Calculated forC₂₀H₂₄N₂O₄: 356.42; Found: 357.2 (M+1).

Synthesis of tert-butyl((2-(3-(hydrazinecarbonyl)-5-methylphenyl)pyridin-4-yl)methyl)carbamate(34)

To a stirred solution of Compound 35 (1.5 g, 4.21 mmol) in EtOH (10 mL)was added hydrazine hydrate (5 mL) and the reaction was allowed to stirat 80° C. for 16 h. After completion (monitored by TLC), water was addedto the reaction mixture and extracted with ethyl acetate. The combinedorganic layer was collected, washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound 36 (1.4 g, 93.33%) as an off-white solid. TLC: 10% MeOH/DCM(R_(f). 0.3). ¹H NMR (400 MHz, DMSO-d₆): δ 9.83 (broad s, 1H), 8.60 (d,J=4.8 Hz, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.85 (s, 1H), 7.70 (s, 1H),7.56 (t, J=5.6 Hz, 1H), 7.22 (d, J=4.4 Hz, 1H), 4.51 (s, 2H), 4.24 (d,J=5.6 Hz, 2H), 2.43 (s, 3H), 1.41 (s, 9H); LCMS Calculated forC₁₉H₂₄N₄O₃: 356.43; Found: 355.13 (M−1).

Synthesis of tert-butyl((2-(3-(2-((2-fluorophenyl)sulfonyl)hydrazine-1-carbonyl)-5-methylphenyl)pyridin-4-yl)methyl)carbamate(37)

To a stirred solution of compound 36 (100 mg, 0.28 mmol) in a 1:1mixture of pyridine and THF (3 mL) was added 2-fluorobenzenesulfonylchloride (60 mg, 0.30 mmol). The reaction was allowed to stir at roomtemperature for 18 h. After completion (monitored by TLC), the reactionmixture was concentrated under high vacuum. The residue was diluted withethyl acetate, quenched with water and extracted. The combined organiclayer was collected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound 37 (110mg, 76.18%) as an off-white solid. TLC: 10% MeOH/DCM (R_(f). 0.6); ¹HNMR (400 MHz, DMSO-d₆): δ 10.82 (s, 1H), 10.33 (d, J=2.0 Hz, 1H), 8.91(d, J=4.8 Hz, 1H), 8.65 (d, J=5.2 Hz, 1H), 8.58-8.52 (m, 1H), 8.16 (s,1H), 8.03 (t, J=7.6 Hz, 1H), 7.91 (s, 1H), 7.81 (t, J=7.6 Hz, 1H),7.69-7.54 (m, 1H), 7.42-7.28 (m, 2H), 7.11 (d, J=7.6 Hz, 1H), 4.28 (d,J=6.0 Hz, 2H), 2.41 (s, 3H), 1.41 (s, 9H); LCMS Calculated forC₂₅H₂₇FN₄O₅S: 514.57; Found: 514.89 (M+1).

Synthesis ofN-(3-(4-(aminomethyl)pyridin-2-yl)-5-methylbenzoyl)-2-fluorobenzenesulfonohydrazide(38)

To a stirred solution of compound 37 (100 mg, 0.19 mmol) in DCM (2 mL)at 0° C., 4N HCl in 1,4-dioxane (0.2 mL) was added and the reaction wasallowed to stir at the room temperature for 12 h. After completion(monitored by TLC), the reaction mixture was quenched with sat. NaHCO₃solution and extracted with DCM. The combined organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure, to afford the title compound 38 (80mg, 91%) as a white solid. TLC: 10% MeOH/DCM (R_(f). 0.3); ¹H NMR (400MHz, DMSO-d₆): δ 10.81 (s, 1H), 10.32 (d, J=2.0 Hz, 1H), 8.91 (d, J=5.2Hz, 1H), 8.72 (d, J=4.8 Hz, 1H), 8.56 (t, J=7.2 Hz, 1H), 8.25 (s, 1H),8.09 (s, 1H), 8.04 (t, J=6.8 Hz, 1H), 7.85-7.79 (m, 1H), 7.72-7.62 (m,1H), 7.50 (d, J=4.8 Hz, 1H), 7.40 (t, J=9.2 Hz, 1H), 7.30 (t, J=7.6 Hz,1H), 7.10 (d, J=7.6 Hz, 1H), 4.16 (q, J=5.6 Hz, 2H), 2.42 (s, 3H); LCMSCalculated for: C₂₀H₁₉FN₄O₃S: 414.46; Found: 415.84 (M+1).

Synthetic Example 12 Synthesis ofN-((2-(3-(2-((2-fluorophenyl)sulfonyl)hydrazine-1-carbonyl)-5-methylphenyl)pyridin-4-yl)methyl)acrylamide

To a stirred solution of compound 38 (100 mg, 0.24 mmol) in DCM (4 mL)at 0° C. was added Et₃N (0.067 mL, 0.48 mmol) followed by apre-dissolved solution of acryloyl chloride (20 mg, 0.21 mmol) in DCM (1mL) and the reaction was allowed to stir at the room temperature for 2h. After completion of the reaction (monitored by TLC), the mixture wasconcentrated under reduced pressure, diluted with ethyl acetate, wateradded and extracted. The organic layer was collected, washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude compound was purified by using prep HPLC to afford the titlecompound (12 mg, 10.6%) as an off-white solid. TLC: 10% MeOH/DCM (R_(f).0.4). (See analytical data in Table 1).

Synthetic Example 13 Synthesis ofN-((2-(3-(2-((2-fluorophenyl)sulfonyl)hydrazine-1-carbonyl)-5-methylphenyl)pyridin-4-yl)methyl)propiolamide

To a stirred solution of compound 38 (100 mg, 0.22 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.11 mL, 0.66 mmol), followed by T₃P (0.31 mL,0.44 mmol). The reaction was allowed to stir at the room temperature for20 min. After, a pre-dissolved solution of propiolic acid (14 mg, 0.22mmol) in DMF (0.5 mL) was added in drop-wise manner and the reactionmixture was stirred at room temperature for 2 h. After completion(monitored by TLC), the solvent was concentrated under high vacuum. Theresidue was quenched with water and extracted with DCM. The organiclayer was collected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byusing prep. HPLC to afford the title compound (5 mg, 4.4%) as anoff-white solid. TLC: 5% MeOH/DCM (R_(f). 0.5); (See Table 1 foranalytical data).

Synthetic Example 14

Synthesis of tert-butyl4-(((2-(((2-fluorophenyl)sulfonyl)carbamoyl)benzofuran-6-yl)methyl)carbamoyl)piperidine-1-carboxylate(37)

To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic(100 mg, 0.43 mmol) in DMF (2 mL) at 0° C. was added DIPEA (221 μL, 0.61mmol), followed by T₃P (201 mg, 1.29 mmol), and 32 (150 mg, 0.43 mmol)was added. The reaction was allowed to stir at the room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas collected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byusing trituration with DCM and n-Pentane to afford compound 39 (134 mg,56%) as a yellow solid. TLC: 10% MeOH/DCM (Rf: 0.5). ¹H NMR (400 MHz,DMSO-d₆): δ 8.42 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz,1H), 7.43 (s, 1H), 7.36-7.34 (m, 1H), 7.25 (s, 1H), 7.20 (d, J=7.6 Hz,1H), 6.76 (s, 1H), 7.38 (d, J=5.2 Hz, 1H), 3.93 (d, J=11.2 Hz, 2H), 2.88(s, 1H), 2.72 (m, 2H), 2.23 (t, J=11.2 Hz, 1H), 1.67 (m, 2H), 1.38 (s,9H), 1.25 (m, 2H); 2 protons not observed; LCMS Calculated forC₂₇H₃₀FN₃O₇S: 559.61; Found: 558.93 (M−1).

Synthesis ofN-((2-(((2-fluorophenyl)sulfonyl)carbamoyl)benzofuran-6-yl)methyl)piperidine-4-carboxamide(40)

To a stirred solution of compound 39 (130 mg, 0.23 mmol) in DCM (2 mL)at 0° C., 4N HCl in 1, 4-dioxane (2 mL) was added and the reactionmixture was allowed to stir at the room temperature for 2 h. Aftercompletion of the reaction (monitored by TLC), the volatiles wereremoved under vacuo, the residue obtained was triturated withDCM/Heptane to afford compound 40 (100 mg, 93%) as an off-white solid.TLC: 5% MeOH/DCM (R_(f). 0.3). ¹H NMR (400 MHz, DMSO-d₆): δ 9.02 (brs,1H), 8.63 (d, J=6.0 Hz, 2H), 8.01 (t, J=7.2 Hz, 1H), 7.96 (s, 1H), 7.77(d, J=8.4 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.37 (s, 1H), 7.26 (d, J=8.0Hz, 1H), 6.89 (s, 1H), 4.40 (d, J=6.0 Hz, 1H), 3.56 (s, 1H), 3.24 (m,2H), 2.88 (m, 2H), 2.33 (m, 1H), 1.86 (m, 2H), 1.74 (m, 2H); LCMSCalculated for C₂₂H₂₂FN₃O₅S: 459.49; Found: 458.63 (M−1).

Synthesis of1-acryloyl-N-((2-(((2-fluorophenyl)sulfonyl)carbamoyl)benzofuran-6-yl)methyl)piperidine-4-carboxamide

To a stirred solution of acrylic acid (20 mg, 0.26 mmol) in DMF (2 mL)at 0° C. was added DIPEA (187 μL, 1.08 mmol), followed by T3P (104 mg,0.32 mmol) and reaction mixture was allowed to stir for 30 min. To theabove reaction mixture was added compound 40 (100 mg, 0.21 mmol) andstirring was continued at room temperature for 2 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure and the crude compound obtained was purified by using prep HPLCto afford the (14 mg, 12.6%) as a white solid. TLC: 10% MeOH/DCM (R_(f).0.5). (See analytical data in Table 1).

Synthetic Examples 15-16

Synthesis of tert-butyl((2-(3-(2-((2,6-dimethoxyphenyl)sulfonyl)hydrazine-1-carbonyl)-5-methylphenyl)pyridin-4-yl)methyl)carbamate(41)

To a stirred solution of compound 36 (450 mg, 1.26 mmol) in THF (10 mL)was added compound 5 (298 mg, 1.26 mmol), followed by Et₃N (0.88 mL,6.32 mmol) and the resulting reaction mixture was allowed to stir atroom temperature for 16 h. After completion (monitored by TLC), thereaction mixture was concentrated under vacuo, crude compound obtainedwas triturated with DCM/pentane to afford the title compound 41 (350 mg,50%) as pale yellow solid. LCMS Calculated for C27H32N4O7S: 556.63;Found: 557.89 (M+1).

Synthesis ofN′-(3-(4-(aminomethyl)pyridin-2-yl)-5-methylbenzoyl)-2,6-dimethoxybenzenesulfonohydrazide(42)

To a stirred solution of compound 41 (400 mg, 0.71 mmol) in DCM (2 mL)at 0° C., 4N HCl in 1,4-dioxane (0.2 mL) was added and the reaction wasallowed to stir at the room temperature for 12 h. After completion(monitored by TLC), the reaction mixture was neutralised using sat.NaHCO₃ solution and extracted with DCM. The combined organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound 42 (250mg, 78.12%) as a white solid. TLC: 10% MeOH/DCM (R_(f). 0.3); LCMSCalculated for: C₂₂H₂₄N₄S₅S: 456.52; Found: 457.01 (M+1).

Synthetic Example 15 Synthesis ofN-((2-(3-(2-((2,6-dimethoxyphenyl)sulfonyl)hydrazine-1-carbonyl)-5-methylphenyl)pyridin-4-yl)methyl)acrylamide

To a stirred solution of acrylic acid (15.15 mg, 0.17 mmol) in DMF (0.8mL) at 0° C. was added DIPEA (0.09 mL, 0.52 mmol) and T₃P (111 mg, 0.35mmol) followed by compound 42 (80 mg, 0.17 mmol) and the reaction wasallowed to stir at the room temperature for 16 h. After completion ofthe reaction (monitored by TLC), the mixture was concentrated underreduced pressure, diluted with ethyl acetate, water added and extracted.The organic layer was collected, washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by using prep HPLC to afford the title compound (12 mg, 13.4%)as a white solid. TLC: 10% MeOH/DCM (Rf 0.6). (See analytical data inTable 1).

Synthetic Example 16 Synthesis ofN-((2-(3-(2-((2,6-dimethoxyphenyl)sulfonyl)hydrazine-1-carbonyl)-5-methylphenyl)pyridin-4-yl)methyl)propiolamide

To a stirred solution of propiolic acid (16.5 mg, 0.23 mmol) in DMF (2mL) at 0° C. was added DIPEA (0.11 mL, 0.59 mmol), followed by T₃P (125mg, 0.39 mmol) and the reaction mixture was allowed to stir at the roomtemperature for 10 min. To the above reaction mixture compound 42 (90mg, 0.22 mmol) was added and the mixture allowed to stir at roomtemperature for 16 h. After completion (monitored by TLC), the reactionmixture was concentrated under vacuo and the residue obtained wasdissolved in DCM and then extracted. The combined organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the crude compound whichwas purified by using prep. HPLC to give title compound (10 mg, 10%) asa white solid. TLC: 10% MeOH/DCM (R_(f). 0.6); (See analytical data forTable 1).

Synthetic Examples 17-19

Synthesis of tert-butyl((1-((3-((2-fluorophenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)carbamate(43)

To a stirred solution of compound 25 (0.3 g, 0.80 mmol) in Pyridine (3mL) at room temperature was added 2-fluorobenzenesulfonyl chloride(0.186 g, 0.96 mmol) and the reaction was allowed to stir at 100° C. for16 h. After completion (reaction monitored by TLC), the reaction mixturewas quenched with 1N HCl, water added and extracted with ethyl acetate.The organic layer was collected, washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The crude compound waspurified by Combi flash column chromatography using a gradient method of4080 EtOAc/Heptane to afford the title compound 43 (0.220 g, 51.52%) asa brown gummy solid. TLC: 80% EtOAc/Heptane (R_(f). 0.35); LCMSCalculated for C₂₄H₂₆FN₅O₆S: 531.56; Found: 530.01 (M−1).

Synthesis ofN-(6-((3-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-fluorobenzenesulfonamide(44)

To a stirred solution of compound 43 (0.22 g, 0.41 mmol) in DCM (3 mL)at 0° C., TFA (0.31 mL, 4.14 mmol) was added, and the reaction wasallowed to stir at room temperature for 2 h. After completion (reactionmonitored by TLC), the reaction mixture was concentrated under reducedpressure to afford the title compound 44 (0.19 g, quant.) as a browngummy solid. TLC: 10% MeOH/DCM (R_(f). 0.3); LCMS Calculated forC₁₉H₁₁FN₅O₄S: 431.44; Found: 432.00 (M+1).

Synthetic Example 17 Synthesis of2-fluoro-N-(4-methoxy-6-((3-(vinylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 44 (160 mg, 0.37 mmol) in DCM (5 mL)was added TEA (0.15 mL, 1.07 mmol) at 0° C. followed by ethene sulfonylchloride (42 mg, 0.33 mmol) and the resulting reaction mixture wasallowed to stir at 0° C. for 1 h. After completion (reaction monitoredby TLC), the reaction mixture was quenched with ice water and extractedwith ethyl acetate. The organic layer was collected, washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude compound was purified by prep HPLC to afford the titlecompound (3.8 mg, 2.03%) as an off-white solid. TLC: 10% MeOH/DCM(R_(f). 0.5). (Analytical data in Table 1)

Synthetic Example 18 Synthesis ofN-((1-((3-((2-fluorophenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)acrylamide

To a stirred solution of acrylic acid (16 mg, 0.22 mmol) in DMF (0.8 mL)at 0° C. was added DIPEA (0.09 mL, 0.52 mmol) and T₃P (86 mg, 0.27 mmol)followed by compound 44 (85 mg, 0.18 mmol), the reaction was allowed tostir at room temperature for 16 h. After completion (reaction monitoredby TLC), the reaction mixture was concentrated under reduced pressure,diluted with ethyl acetate, water added and extracted. The organic layerwas collected, washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The crude compound was purified byusing Chiral HPLC to afford the title compound (18 mg, 19%) as a whitesolid. TLC: 10% MeOH/DCM (R_(f). 0.6). (Analytical data in Table 1).

Synthesis of tert-butyl((1-((3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)carbamate(45)

To a stirred solution of compound 25 (0.3 g, 0.80 mmol) in 1,4-dioxane(5 mL) was added compound 2,6-dimethoxybenzenesulfonyl chloride (0.379g, 1.60 mmol), followed by NaO^(t)Pn (0.264 g, 2.40 mmol) and theresulting reaction mixture was allowed to stir at 100° C. for 16 h.After completion (reaction monitored by TLC), the reaction mixture wasquenched with ice water and extracted with ethyl acetate. The organiclayer was collected, washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The crude compound was purified byusing combi flash gradient 70-80% ethyl acetate. to afford the titlecompound 45 (80 mg, 17.46%) as a brown solid. TLC: 10% MeOH/DCM (R_(f).0.6). LCMS Calculated for C₂₆H₃₁N₅O₈S: 573.62; Found: 572.06 (M−1).

Synthesis ofN-(6-((3-(aminomethyl)-1H-pyrazol-1-yl)methyl)4methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide(46)

To a stirred solution of compound 45 (0.15 g, 0.26 mmol) in DCM (3 mL)at 0° C., TFA (0.20 mL, 2.61 mmol) was added, and the reaction wasallowed to stir at room temperature for 2 h. After completion (reactionmonitored by TLC), the reaction mixture was concentrated under reducedpressure to afford the title compound 46 (0.13 g, quant.) as a browngummy solid. TLC: 5% MeOH/DCM (R_(f). 0.3). LCMS Calculated forC₂₁H₂₃N₅O₆S: 473.50; Found: N.A.

Synthetic Example 19 Synthesis of2,6-dimethoxy-N-(4-methoxy-6-((3-(vinylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 46 (110 mg, 0.23 mmol) in DCM (6 mL)was added TEA (0.088 mL, 0.63 mmol) at 0° C., followed by ethenesulfonyl chloride (26 mg, 0.20 mmol) and the resulting reaction mixturewas allowed to stir at room temperature for 1 h. After completion(reaction monitored by TLC), the reaction mixture was quenched with icewater and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The crude compound was purified by using prep HPLC toafford the title compound (3 mg, 2.54%) as an off-white solid. TLC: 5%MeOH/DCM (R_(f). 0.5). (Analytical data in Table 1).

Synthetic Examples 20-21

Synthesis of tert-butyl((1-((4-methoxy-3-((phenylmethyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)carbamate(47)

To a stirred solution of compound 25 (0.3 g, 0.80 mmol) in Pyridine (3mL) at room temperature, was added phenylmethanesulfonyl chloride (0.18g, 0.96 mmol) and the reaction was allowed to stir at 100° C. for 16 h.After completion (reaction monitored by TLC), the reaction mixture wascooled to room temperature, quenched with 1N HCl, and extracted withethyl acetate. The organic layer was collected, washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Thecrude compound was purified by Combi flash column chromatography using agradient method of 40-80% EtOAc/Heptane to afford the title compound 47(0.220 g, 51.52%) as a brown gummy solid. TLC: 80% EtOAc/Heptane (R_(f).0.35). LCMS Calculated for C₂₅H₂₉N₅O₆S: 527.60; Found: 428.84 (M−Boc+1).

Synthesis ofN-(4-methoxy-6-((3-(((2,2,2-trifluoroacetyl)-14-azaneyl)methyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)-1-phenylmethanesulfonamide(48)

To a stirred solution of compound 47 (0.22 g, 0.51 mmol) in DCM (3 mL)at 0° C., TFA (0.39 mL, 5.14 mmol) was added, and the reaction wasallowed to stir at room temperature for 1 h. After completion of thereaction (monitored by TLC), concentrated under reduced pressure toafford the title compound 48 (0.18 g, quant.) as a brown gummy solid. Apart of it was purified by prep HPLC to afford the title compound (6 mg,11.36%) as an off-white solid. TLC: 5% MeOH/DCM (R_(f). 0.5). This wasthe pure regioisomer, as drawn. TLC: 10% MeOH/DCM (R_(f). 0.5). LCMSCalculated for C₂₀H₂₁N₅O₄S: 427.48: Found: 428.2 (M+1).

Synthetic Example 20 Synthesis ofN-((1-((4-methoxy-3-((phenylmethyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)acrylamide

To a stirred solution of compound 48 (120 mg, 0.28 mmol) in DCM (5 mL)at 0° C. was added TEA (0.12 mL, 0.84 mmol) followed by acryloylchloride (25 mg, 0.28 mmol) and the resulting reaction mixture wasallowed to stir at the same temperature for 30 min. After completion(reaction monitored by TLC), the reaction mixture was quenched with icewater and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The crude compound was purified by prep HPLC to affordthe title compound (12 mg, 8.8%) as an off-white solid. TLC: 10%MeOH/DCM (R_(f). 0.5). (See analytical data for Table 1)

Synthetic Example 21 Synthesis ofN-((1-((4-methoxy-3-((phenylmethyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)ethenesulfonamide

To a stirred solution of compound 48 (120 mg, 0.28 mmol) in DCM (3 mL)at 0° C. was added TEA (0.12 mL, 0.84 mmol) followed by ethene sulfonylchloride (42 mg, 0.33 mmol) and the reaction mixture was allowed to stirat the same temperature for 2 h. After completion (reaction monitored byTLC), the reaction mixture was quenched with ice water and extractedwith ethyl acetate. The organic layer was collected, washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude compound was purified by prep HPLC to afford the titlecompound (5 mg, 3.4%) as an off-white solid. TLC: 10% MeOH/DCM (R_(f).0.5). (Analytical data in Table 1).

Synthetic Example 22

Synthesis of tert-butyl((1-((4methoxy3((2methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)carbamate(49)

To a stirred solution of compound 25 (0.45 g, 1.20 mmol) in THF (5 mL)was added 2-methoxybenzenesulfonyl chloride (0.49 g, 2.41 mmol),followed by NaO^(t)Pn (0.396 g, 3.60 mmol) and the resulting reactionmixture was allowed to stir at 60° C. for 16 h. After completion(reaction monitored by TLC), the reaction mixture was quenched with icewater and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The crude compound was purified Combi flashchromatography using a gradient method of 60-80% ethyl acetate/Heptaneto afford the title compound 49 (0.130 g, 19.9%) as a brown gummy solid.TLC: 5% MeOH/DCM (R_(f). 0.6). LCMS Calculated for C₂₅H₂₉N₅O₇S: 543.60;Found: 542.1 (M−1).

Synthesis of2-methoxy-N-(4-methoxy-6-((3-(((2,2,2-trifluoroacetyl)-14-azaneyl)methyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(50)

To a stirred solution of compound 49 (0.13 g, 0.23 mmol) in DCM (3 mL)at 0° C., TFA (0.18 mL, 2.39 mmol) was added, and the reaction wasallowed to stir at room temperature for 2 h. After completion (reactionmonitored by TLC), reaction mixture was concentrated under reducedpressure to afford the title compound 50 (0.1 g, 94.3%) as a brown semisolid. TLC: 10% MeOH/DCM (R_(f). 0.5). LCMS Calculated for C₂₀H₂₁N₅O₅S:443.48: Found: 442.4 (M−1).

Synthesis of2-methoxy-N-(4-methoxy-6-((3-(vinylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 50 (0.1 g, 0.22 mmol) in DCM (3 mL)was added TEA (0.1 mL, 0.66 mmol) at 0° C. followed by ethene sulfonylchloride (27.85 mg, 0.22 mmol) and the resulting reaction mixture wasallowed to stir at the same temperature for 2 h. After completion(reaction monitored by TLC), reaction mixture was quenched with icewater and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The crude compound was purified by prep HPLC to affordthe title compound (6 mg, 5%) as an off-white solid. TLC: 10% MeOH/DCM(R_(f). 0.5). (Analytical data in Table 1).

Synthetic Examples 23-24

Synthetic Example 23 Synthesis ofN-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)-2-fluoroacrylamide

To a stirred solution of Compound 26a (150 mg, 0.34 mmol) in DMF (3 mL)at 0° C. was added TEA (0.14 mL, 1.03 mmol) and T₃P (162 mg, 0.51 mmol),followed by 2-fluoroacrylic acid (30.6 mg, 0.34 mmol). The reaction wasallowed to stir at room temperature for 16 h. After completion (reactionmonitored by TLC), the reaction mixture was concentrated under reducedpressure, diluted with ethyl acetate, water added and extracted. Theorganic layer was collected, washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The crude compound waspurified by using prep HPLC to afford the title compound (8.0 mg, 4.5%)as an off-white solid. TLC: 10% MeOH/DCM (R_(f). 0.6). (Analytical datain Table 1).

Synthetic Example 24 Synthesis ofN-((1-((3-((cyclohexylmethyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-3-yl)methyl)ethenesulfonamide

To a stirred solution of compound 26a (15 mg, 0.35 mmol) in DCM (3 mL)was added TEA (0.01 mL, 0.103 mmol) at 0° C. followed by ethene sulfonylchloride (44 mg, 0.35 mmol) and the reaction mixture was allowed to stirat room temperature for 2 h. After completion of the reaction (monitoredby TLC), the reaction mixture was concentrated under reduced pressureand the crude compound was purified by prep HPLC to afford the titlecompound (5.8 mg, 32%) as an off-white solid. TLC: 80% EtOAc/Heptane(R_(f). 0.5). (Analytical data in Table 1).

Synthetic Examples 25A and 25B, 26A and 26B, and 27A and 27B

Synthesis of tert-butyl1-((3-((2,6-dimethoxyphenyl)sulfonamido)-4methoxybenzo[d]isoxazol-6-yl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate(51 and its regioisomer)

To a stirred solution of compound 17 (0.22 g, 0.57 mmol) in THF (5 mL)was added NaO^(t)Pn (0.377 g, 3.42 mmol) followed by2,6-dimethoxybenzenesulfonyl chloride (0.405 g, 1.71 mmol) and thereaction mixture was allowed to stir at room temperature for 16 h. Aftercompletion (reaction monitored by TLC), the reaction mixture wasquenched with ice water and extracted with ethyl acetate. The organiclayer was collected, washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The crude compound was purified bycombi flash chromatography using gradient method of 50-80% ethylacetate/Heptane to afford the title compound 51 (91 mg, 27.22%, isolatedas inseparable regio-isomeric mixture) as a gummy brown solid. TLC: 5%MeOH/DCM (R_(f). 0.6). LCMS Calculated for C₂₇H₃₁N₅O₈S: 585.63; Found:586.2 (M+1). ¹H NMR is complicated and indicates a regio-isomericmixture.

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-((5-(2,2,2-trifluoroacetyl)-5,6-dihydro-514-pyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(52 and its regioisomer)

To a stirred solution of compound 51 (0.1 g, 0.17 mmol) in DCM (1 mL) at0° C., TFA (0.13 mL, 1.70 mmol) was added, and the reaction was allowedto stir at room temperature for 2 h. After completion (reactionmonitored by TLC), the reaction mixture was concentrated under reducedpressure to afford the residue was triturated with ether and dried undervacuum to afford the title mixture of isomers compound 52 (120 mg,crude, isolated as inseparable regio-isomeric mixture) as a brown oil.TLC: 5% MeOH/DCM (R_(f). 0.3). LCMS Calculated for C₂₂H₂₃N₅O₆S: 485.52:Found: 486.50 (M+1). ¹H NMR is complicated and indicates aregio-isomeric mixture.

Synthetic Examples 25A and 25B Synthesis of2,6-dimethoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamideand2,6-dimethoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 52 (0.13 g, 0.26 mmol) in DMF (1.5 mL)at 0° C. was added DIPEA (0.16 mL, 0.937 mmol) and T₃P (0.166 g, 0.52mmol) followed by propiolic acid (21 mg, 0.309 mmol) and the reactionwas allowed to stir at room temperature for 16 h. After completion(reaction monitored by TLC), the reaction mixture was concentrated underreduced pressure, quenched with ice water and extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure. The crudecompound was purified by using chiral HPLC to afford the title compound2,6-dimethoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(7 mg, 5%) as an off white solid and2,6-dimethoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(8 mg, 5.5%) as an off-white solid. TLC: 5% MeOH/DCM (R_(f). 0.6).(Analytical data in Table 1).

Synthesis of tert-butyl1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate(53 and its regioisomer)

To a stirred solution of compound 17 (0.3 g, 0.77 mmol) in THF (5 mL)was added 2-methoxybenzenesulfonyl chloride (0.320 g, 1.55 mmol),followed by NaO^(t)Pn (0.428 g, 3.89 mmol) and the resulting reactionmixture was allowed to stir at room temperature for 16 h. Aftercompletion (reaction monitored by TLC), the reaction was quenched withice water and extracted with ethyl acetate. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The crude compound was purified bycombi flash chromatography using a gradient method of 70-80% ethylacetate/Heptane to afford the title compound 53 (310 mg, 71.75%,isolated as inseparable regio-isomeric mixture) as brown solid. TLC: 5%MeOH/DCM (R_(f). 0.6). LCMS Calculated for C₂₆H₂₉N₅O₇S: 555.61; Found:556.2 (M+1). ¹H NMR is complicated and indicates a regio-isomericmixture.

Synthesis of2-methoxy-N-(4-methoxy-6-((5-(2,2,2-trifluoroacetyl)-5,6-dihydro-514-pyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(54 and its regioisomer)

To a stirred solution of compound 53 (0.4 g, 0.72 mmol) in DCM (4 mL) at0° C., TFA (0.54 mL, 7.2 mmol) was added, and the reaction was allowedto stir at room temperature for 2 h. After completion (reactionmonitored by TLC), the reaction mixture was concentrated under reducedpressure to obtain the residue, which was triturated with ether anddried under vacuum to afford the title compound 54 (410 mg, crude,isolated as inseparable regio-isomeric mixture) as a brown solid. TLC:10% MeOH/DCM (R_(f). 0.5). LCMS Calculated for C₂₁H₂₁N₅O₅S: 455.49:Found: 454.3 (M−1). ¹H NMR is complicated and indicates a regio-isomericmixture.

Synthetic Examples 26A and 26B Synthesis of2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamideand2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 54 (0.2 g, 0.43 mmol) in DMF (3 mL) at0° C. was added DIPEA (0.22 mL, 1.3 mmol) and T₃P (0.27 g, 0.86 mmol),followed by propiolic acid (30 mg, 0.43 mmol). The reaction was allowedto stir at room temperature for 16 h. After completion (reactionmonitored by TLC), the reaction mixture was concentrated under reducedpressure, quenched with ice water and extracted with ethyl acetate. Theorganic layer was collected, washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The crude compound waspurified by using chiral HPLC to afford the title compounds2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(17 mg, 7.6%) as an off white solid and2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(19mg, 8.55%) as an off-white solid. TLC: 5% MeOH/DCM (R_(f). 0.6).(Analytical data in Table 1).

Synthetic Examples 27B and 27A Synthesis of2-methoxy-N-(4-methoxy-6-((5-(vinylsulfonyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamideand2-methoxy-N-(4-methoxy-6-((5-(vinylsulfonyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 54 (0.5 g, 1.09 mmol) in DCM (4 mL)was added TEA (0.65 mL, 4.52 mmol) at 0° C. followed by ethenesulfonylchloride (343 mg, 2.71 mmol) and the resulting reaction mixture wasallowed to stir at the same temperature for 1 h. After completion of thereaction (monitored by TLC), reaction mixture was quench with ice waterand extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by using chiral HPLCto afford the title compound 27b (12 mg, 2.02%) as an off white solidand 27a (9 mg, 1.51%) as an off-white solid. TLC: 5% MeOH/DCM (R_(f).0.6). (Analytical data in Table 1).

Synthetic Examples 28A, 28B, 29A, 29B, 30A and 30B

Synthetic Examples 28A and 28B Synthesis of Synthesis of1-cyclohexyl-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide and1-cyclohexyl-N-(6-((5,6-dihydropyrrolo[13,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide

To a stirred solution of compound 18 (180 mg, 0.33 mmol) in DCM (3 mL)was added TFA (0.13 mL, 1.73 mmol) at 0° C. and the reaction was allowedto stir at room temperature for 4 h. After completion of the reaction(monitored by TLC), the reaction mixture was basified with sat. NaHCO₃solution and extracted with DCM. The organic layer was collected, washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to obtain crude residue, which was triturated with di-ethylether/pentane to afford (100 mg, 67.10%, isolated as inseparableregioisomeric mixture) as a white solid which was purified using chiralHPLC to get the title compounds 28a: (6.5 mg, 4.42) as a white solid and28b: (12 mg, 8.16%) as a white solid. LCMS Calculated for C₂₁H₂₇NO₄S:445.54; Found: 446.50 (M+1). (Analytical data in Table 1).

Synthetic Examples 29A and 29B Synthesis ofN-(6-((5-acryloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide andN-(6-((5-acryloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide

To a stirred solution of compound 18a (150 mg, 0.33 mmol) in DMF (1.5mL) at 0° C. was added DIPEA (0.17 mL, 0.96 mmol), followed by T3P (175mg, 0.55 mmol) and the contents were allowed to stir at room temperaturefor 20 min. After, a pre-dissolved solution of acrylic acid (22 mg, 0.31mmol) in DMF (0.5 mL) was added in a drop-wise manner and the reactionmixture was stirred at room temperature for 16 h. After completion(reaction monitored by TLC), the reaction mixture was concentrated underreduced pressure, water added and extracted with ethyl acetate. Theorganic layer was collected, washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by using chiral HPLC to afford the title compoundsN-(6-((5-acryloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide(4 mg, 2.4%) as an off-white solid andN-(6-((5-acryloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide(6 mg, 3.6%) as an off-white solid. TLC: 5% MeOH/DCM (R_(f). 0.5).(Analytical data in Table 1).

Synthetic Examples 30A and 30B Synthesis of1-cyclohexyl-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)methanesulfonamideand1-cyclohexyl-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)methanesulfonamide

To a stirred solution of1-cyclohexyl-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide1-cyclohexyl-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)methanesulfonamide(130 mg, 0.29 mmol) in DMF (1 mL) at 0° C. was added DIPEA (0.15 mL,0.87 mmol), followed by T₃P (138 mg, 0.43 mmol) and the contents wereallowed to stir at room temperature for 20 min. After, a pre-dissolvedsolution of propiolic acid (20 mg, 0.29 mmol) in DMF (0.5 mL) was addedin a drop-wise manner and the reaction mixture was stirred at roomtemperature for 2 h. After completion (reaction monitored by TLC), thereaction mixture was concentrated under high vacuum. The residue wasquenched with water and extracted with DCM. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byusing reverse phase HPLC to obtain (16.5 mg, 11.36%, isolated asinseparable regio-isomeric mixture) as an off-white solid. TLC: 5%MeOH/DCM (R_(f). 0.5). The regio-isomeric mixture was again purified bychiral HPLC to afford the tile compounds as 30a (8 mg, 5.5%) as anoff-white solid and 30b (8.5 mg, 5.8%) as an off-white solid (Analyticaldata in Table 1).

Synthetic Examples 31-35

Synthesis of tert-butyl((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(55)

To a stirred solution of compound 22 (0.250 g, 0.66 mmol) in THF (4 mL)at 0° C. was added KO^(t)Bu (0.225 g, 2.01 mmol), followed by2-methoxybenzenesulfonyl chloride (0.166 g, 0.80 mmol) and the reactionwas allowed to stir at 60° C. for 16 h. After completion of the reaction(monitored by TLC), the reaction mixture was diluted with DCM, wateradded and extracted. The organic layer was collected, washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude compound was purified by Combi flash column chromatographyusing a gradient method of 40-60% EtOAc/Heptane to afford the titlecompound 55 (0.081 g, 22.3%) as a white solid. TLC: 100% EtOAc (R_(f).0.35). ¹H NMR (400 MHz, DMSO-d₆): δ 10.10 (s, 1H), 7.79 (dd, J=8.0, 1.6Hz, 1H), 7.67 (s, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.20 (d,J=8.0 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 5.37(s, 2H), 3.95 (d, J=5.6 Hz, 2H), 3.98 (s, 3H), 3.78 (s, 3H), 1.36 (s,9H); LCMS Calculated for C₂₅H₂₉N₅O₇S: 543.60; Found: 545.2 (M+2).

Synthesis ofN-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)4methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride (56)

To a stirred solution of compound 55 (80 mg, 0.147 mmol) in DCM (2 mL)at 0° C., 4M HCl in 1,4-dioxane (0.15 mL, 0.589 mmol) was added, and thereaction was allowed to stir at room temperature for 2 h. Aftercompletion (reaction monitored by TLC), the reaction mixture wasconcentrated under reduced pressure to afford the title compound 56 (70mg, 98%, HCl salt) as an off-white solid. TLC: 10% MeOH/DCM (R_(f).0.5). ¹H NMR (400 MHz, DMSO-d₆): δ10.17 (s, 1H), 8.02 (broad s, 2H),7.91 (s, 1H), 7.80 (d, J=7.6 Hz, 2H), 7.65 (t, J=8.4 Hz, 1H), 7.57 (s,1H), 7.21 (d, J=8.4 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 6.85 (s, 1H), 6.80(s, 1H), 5.44 (s, 2H), 3.89 (d, J=5.6 Hz, 2H), 3.84 (s, 3H), 3.79 (s,3H); LCMS Calculated for C₂₀H₂₂ClN₅O₅S: 479.94; Found: 444.08 (M+1). Thesalt was taken forward to the next step without any furtherpurification.

Synthetic Example 31 Synthesis of N-((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl)propiolamide

To a stirred solution of compound 56 (70 mg, 0.145 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.08 mL, 0.437 mmol), followed by T₃P (69 mg,0.217 mmol) and the contents were allowed to stir at room temperaturefor 20 min. After that, a pre-dissolved solution of propiolic acid (15.2mg, 0.217 mmol) in DMF (0.5 mL) was added in drop-wise manner and thereaction was stirred at room temperature for 16 h. After completion(monitored by TLC), the reaction mixture was quenched with water andextracted with ethyl acetate. The organic layer was collected, washedwith brine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The crude compound was purified by prep. HPLC to afford thetitle compound (27 mg, 37.3%) as an off-white solid. TLC: 5% MeOH/DCM(Rf 0.5). (Analytical data in Table 1).

Synthetic Example 32 Synthesis of2-methoxy-N-(4-methoxy-6-((4-(vinylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 56 (70 mg, 0.145 mmol) in DCM (4 mL)at 0° C. was added TEA (0.06 mL, 0.435 mmol) followed by ethenesulfonylchloride (19 mg, 0.15 mmol) and the resulting reaction mixture wasallowed to stir at the same temperature for 1 h. After completion(reaction monitored by TLC), the reaction mixture was quenched with icewater and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The crude compound was purified by prep HPLC to affordthe title compound (1 mg, 1.2%) as a white solid. TLC: 100% E. A.(R_(f). 0.5). (Analytical data in Table 1).

Synthetic Example 33 Synthesis of tert-butyl((1-((3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(57)

To a stirred solution of compound 22 (1 g, 2.67 mmol) in THF (20 mL) wasadded KOtBu (8.0 mL, 8.03 mmol) followed by 2,6-dimethoxybenzenesulfonylchloride (950 mg, 4.02 mmol) and the reaction mixture was allowed tostir at the room temperature for 16 h. After completion (monitored byTLC), the reaction mixture was quenched with ice water and extractedwith ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude compound was purifiedby combi flash chromatography (neutral alumina) to afford compound 57(650 mg, 42.310%) as an off-white solid. TLC: 100 EtOAc (Rf: 0.6). LCMSCalculated for C26H31N5O8S: 573.19; Found: 573.30 (M+).

Synthesis ofN-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamidehydrochloride (58)

To a stirred solution of compound 57 (0.65 g, 1.13 mmol) in DCM (3 mL)at 0° C. was added 4M HCl in 1,4-Dioxane (1.4 mL, 5.66 mmol). Thereaction was allowed to stir at room temperature for 2 h. Aftercompletion (reaction monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. The crude was washed with Et₂₀ toafford the title compound 58 (500 mg, 87.0%) as an off-white solid. TLC:10% MeOH/DCM (Rf: 0.1). LCMS Calculated for C21H23N5O6S: 473.14; Found:474.30 (M+1).

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-((4-(vinylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 58 (70 mg, 0.137 mmol) in DCM (4 mL)at 0° C. was added TEA (0.06 mL, 0.411 mmol), followed by ethenesulfonyl chloride (19 mg, 0.15 mmol) and the reaction mixture wasallowed to stir at 0° C. for 1 h. After completion (reaction monitoredby TLC), the reaction mixture was quenched with ice water and extractedwith ethyl acetate. The organic layer was collected, washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude compound was purified by prep HPLC to afford the titlecompound (7.6 mg, 9.87%) as a white solid. TLC: 100% E.A. (Rf 0.5).(Analytical data in Table 1).

Synthetic Example 34 Synthesis of N-((1-((3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide

To a stirred solution of compound 58 (60 mg, 0.117 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.063 mL, 0.353 mmol), followed by T₃P (44.5mg, 0.140 mmol) and the contents were stirred at room temperature for 5min. After that, a pre-dissolved solution of propiolic acid (12.2 mg,0.175 mmol) in DMF (0.5 mL) was added in a drop-wise manner and thereaction was allowed to stir at room temperature for 12 h. Aftercompletion (monitored by TLC), the reaction mixture concentrated underreduced pressure. The crude compound was purified by using prep HPLC toafford the title compound (7 mg, 11.3%) as a white solid. TLC: 10%MeOH/DCM (R_(f). 0.5). (Analytical data in Table 1).

Synthetic Example 35 Synthesis of tert-butyl((1-((4methoxy-3-((3-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (59)

To a stirred solution of compound 22 (0.400 g, 1.07 mmol) in THF (4 mL)at room temperature was added NaO^(t)Pn (0.353 g, 3.21 mmol) and thecontents were stirred for 15 min. 3-Methoxybenzenesulfonyl chloride(0.33 g, 1.60 mmol) was added at room temperature and the reaction wasallowed to stir at 80° C. for 16 h. After completion of the reaction(monitored by TLC), the reaction mixture was cooled to 0° C., quenchedwith ice water and extracted with ethyl acetate. The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by using combi flashchromatography using a gradient of 70-80% ethyl acetate/Heptane toafford the title compound 59 (248 mg, 42.6%) as a white solid. TLC: 50%EtOAc/Heptane (R_(f). 0.2); LCMS Calculated for C₂₅H₂₉N₅O₇S: 543.60:Found: 544.2 (M+1).

Synthesis ofN-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)4methoxybenzo[d]isoxazol-3-yl)-3-methoxybenzenesulfonamide(60)

To a stirred solution of compound 59 (0.4 g, 0.76 mmol) in 1,4-Dioxane(1 mL) at 0° C., a 4M HCl in 1,4-Dioxane (0.4 mL) was added and thereaction was allowed to stir at room temperature for 3 h. Aftercompletion (reaction monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and washed with DiethylEther/Heptane to afford the title compound 60 (250 mg, 70.8%) as palebrown solid. TLC: 10% MeOH/DCM (R_(f). 0.5). ¹H NMR (400 MHz, DMSO-d₆):δ 10.17 (s, 1H), 8.10 (br s, 3H), 7.92 (s, 2H), 7.59-7.50 (m, 4H), 7.25(d, J=6.8 Hz, 1H), 6.87 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 3.86 (s,3H), 3.80 (s, 3H); LCMS Calculated for C₂₀H₂₂ClN₅O₅S: 540.49; Found:444.08 (Freebase+1).

Synthesis ofN-((1-((4-methoxy-3-((3-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide

To a stirred solution of compound 60 (125 mg, 0.260 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.14 mL, 0.84 mmol), followed by T₃P (270 mg,0.846 mmol) and the reaction was allowed to stir at room temperature for5 min. After that, a pre-dissolved solution of propiolic acid (39.5 mg,0.56 mmol) in DMF (0.5 mL) was added in drop-wise manner and thereaction was allowed to stir at room temperature for 16 h. Aftercompletion (reaction monitored by TLC), the reaction mixture wasquenched with ice-water and extracted with ethyl acetate. The organiclayer was collected, washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The crude compound was purified byprep. HPLC to afford the title compound (14.2 mg, 11.02%) as a whitesolid. TLC: 10% MeOH/DCM (R_(f). 0.5). (Analytical data in Table 1).

Synthetic Examples 36-38

Synthesis of methyl2-(N-(6-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)benzoate(61)

To a stirred solution of compound 22 (1 g, 2.67 mmol) in THF (10 mL) at0° C. was added a 1M solution of KO^(t)Bu in THF (8 mL, 8.03 mmol),followed by methyl methyl-2-(chlorosulfonyl)benzoate (1.25 g, 5.34 mmol)and the reaction was allowed to stir at the same temperature for 2 h.After completion of the reaction (monitored by TLC), the reactionmixture was diluted with ethyl acetate, water added and extracted. Theorganic layer was collected, washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The crude compound waspurified by Combi flash column chromatography using a gradient method of40-50% EtOAc/Heptane to afford the title compound 61 (0.065 g, 43.9%) asa brown solid. TLC: 70% EtOAc (R_(f). 0.35). ¹H NMR (400 MHz, DMSO-d₆):δ 10.36 (br s, 1H), 8.06-8.04 (m, 1H), 7.76-7.67 (m, 4H), 7.35 (s, 1H),7.11 (s, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.72 (t, J=7.2 Hz, 1H), 5.36 (s,2H), 3.95 (t, J=5.6 Hz, 2H), 3.80 (s, 6H, merged), 1.35 (s, 9H); LCMSCalculated for C₂₆H₂₉N₅O₈S: 571.61; Found: 572.20 (M+1).

Synthesis of methyl2-(N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)benzoate(62)

To a stirred solution of compound 61 (100 mg, 1.75 mmol) in DCM (3 mL)at 0° C., TFA (1.32 mL, 17.51 mmol) was added and the reaction wasallowed to stir at room temperature for 2 h. After completion (reactionmonitored by TLC), reaction mixture was concentrated under reducedpressure to afford the title compound 62 (75 mg, 90.90%) as a browngummy solid. TLC: 10% MeOH/DCM (R_(f). 0.5). LCMS Calculated forC₂₁H₂₁N₅O₆S: 471.50; Found: 472.3 (M+1).

Synthetic Example 36 Synthesis of methyl2-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)sulfamoyl)benzoate

To a stirred solution of compound 62 (100 mg, 0.21 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.11 mL, 0.63 mmol), followed by T₃P (87 mg,0.27 mmol) and the contents were allowed to stir at room temperature for20 min. After, a pre-dissolved solution of propiolic acid (14.7 mg,0.211 mmol) in DMF (0.3 mL) was added in drop-wise manner and thereaction was stirred at room temperature for 4 h. After completion(reaction monitored by TLC), the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The crude compound was purified by prep. HPLC toafford the title compound (8.5 mg, 7.7%) as an off white solid. TLC: 10%MeOH/DCM (R_(f). 0.5). (Analytical data in Table 1).

Synthetic Example 37 Synthesis of2-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)sulfamoyl)benzoicacid

To a stirred solution of methyl2-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)sulfamoyl)benzoate(100 mg, 0.19 mmol) in a 1:1 mixture of THF-H₂O (2 mL), LiOH (13 mg,0.57 mmol) was added and the reaction mixture was stirred at roomtemperature for 16 h. The progress of the reaction was monitored by TLC.After completion, the reaction mixture was concentrated under reducedpressure. The residue was neutralized with 1N HCl and extracted withethyl acetate. The organic layer was collected, washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure to affordthe title compound (6 mg, 6.16%) as an off white solid. TLC: 100%EtOAc/Heptane (R_(f). 0.2) (Analytical data in Table 1).

Synthesis of methyl 4-(N-(6-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)benzoate(63)

To a stirred solution of compound 22 (0.50 g, 1.33 mmol) in THF (4 mL)at 0° C. was added a 1M solution of KO^(t)Bu in THF (4 mL, 4.01 mmol),followed by methyl 4-(chlorosulfonyl) benzoate (0.63 g, 2.67 mmol) andthe reaction was allowed to stir at room temperature for 4 h. Aftercompletion (reaction monitored by TLC), the reaction mixture was dilutedwith ethyl acetate, water added and extracted. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byCombi flash column chromatography using a gradient method of 40-60%EtOAc/Heptane to afford the title compound 63 (0.090 g, 11.71%) as awhite solid. TLC: 100% EtOAc (R_(f). 0.35). ¹H NMR (400 MHz, DMSO-d₆): δ10.10 (s, 1H), 7.81-7.79 (dd, J=7.6, 2.0 Hz, 1H), 7.67 (s, 1H), 7.63 (t,J=8.0 Hz, 1H), 7.35 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.10 (t, J=8.0 Hz,1H), 6.82 (s, 1H), 6.74 (s, 1H), 5.37 (s, 1H), 3.95 (d, J=5.6 Hz, 2H),3.78 (s, 3H), 3.28 (s, 3H), 1.36 (s, 9H), 1.25 (m, 2H); LCMS Calculatedfor C₂₆H₂₉N₅O₈S: 571.61; Found: 572.2 (M+1).

Synthesis of methyl 4-(N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)benzoate (64)

To a stirred solution of compound 63 (0.2 g, 0.35 mmol) in DCM (3 mL) at0° C., TFA (0.4 mL, 3.49 mmol) was added, and the reaction was allowedto stir at room temperature for 2 h. After completion (reactionmonitored by TLC), the reaction mixture was concentrated under reducedpressure to afford the title compound 64 (150 mg, 90.9%) as a browngummy solid. TLC: 10% MeOH/DCM (R_(f). 0.5). LCMS Calculated forC₂₁H₂₁N₅O₆S: 471.49; Found: 472.2 (M+1).

Synthetic Example 38 Synthesis of methyl4-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)sulfamoyl)benzoate

To a stirred solution of compound 64 (100 mg, 0.21 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.1 mL, 0.53 mmol), followed by T₃P (100 mg,0.31 mmol) and the contents were allowed to stir at room temperature for20 min. After that, a pre-dissolved solution of propiolic acid (15 mg,0.217 mmol) in DMF (0.5 mL) was added in drop-wise manner and thereaction was stirred at room temperature for 4 h. After completion(reaction monitored by TLC), the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure. The crude compound was purified by using prep. HPLC toafford the title compound (2.5 mg, 2.71%) as an off white solid. TLC: 5%MeOH/DCM (R_(f). 0.5). (Analytical data in Table 1).

Synthetic Example 39

Synthesis of tert-butyl acryloylglycinate (67)

To a stirred solution of 66 (0.500 g, 2.99 mmol) in DCM (10 mL) at 0° C.was added DIPEA (1.55 mL, 8.97 mmol) followed by acryloyl chloride (0.4g, 4.49 mmol). The reaction mixture was stirred at room temperature for1 h. After completion (reaction monitored by TLC), water was added andextracted with DCM. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the title compound 67(581 mg, quant.) as a yellow liquid, which was used in the next reactionwithout further purification. TLC: 5% MeOH/DCM (R_(f). 0.5). ¹H NMR (400MHz, DMSO-d₆): δ 8.40 (brs, 1H), 6.25 (q, J=10.0 Hz, 1H), 6.10 (dd,J=16.0, 2.0 Hz, 1H), 5.62 (d, J=2.4 Hz, 1H), 3.79 (d, J=6.4 Hz, 2H),1.39 (s, 9H); LCMS Calculated for C₉H₁₅NO₃: 185.22; Found: 187.20 (M+2).

Synthesis of acryloylglycine (65)

To a stirred solution of compound 67 (560 mg, 3.02 mmol) in DCM (5 mL)at 0° C. was added TFA (0.47 mL, 6.05 mmol) and the reaction was allowedto stir at room temperature for 1 h. After completion of the reaction(monitored by TLC), reaction mixture was concentrated under reducedpressure to obtain a residue which was triturated with di-ethylether/pentane to afford 65 (420 mg, quant.) as a yellow solid which wasused in the next reaction without further purification. TLC: 10%MeOH/DCM (R_(f). 0.6). ¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (brs, 1H), 6.28(q, J=10.0 Hz, 1H), 6.12 (d, J=16.8 Hz, 1H), 5.62 (d, J=10.0 Hz, 1H),3.83 (d, J=5.2 Hz, 2H). ¹H-NMR didn't hint acid proton. LCMS Calculatedfor C₅H₇NO₃: 129.12; Found: 257.05 (2M-1).

Synthesis of6-((2-acrylamidoacetamido)methyl)-N-((2-fluorophenyl)sulfonyl)benzofuran-2-carboxamide

To a stirred solution of 32 (200 mg, 0.57 mmol) in DMF (5 mL) at 0° C.was added DIPEA (0.294 mL, 1.71 mmol), followed by T₃P (0.273 mg, 0.86mmol) and the contents were allowed to stir at room temperature for 20min. After, Compound 65 (112 mg, 0.86 mmol) was added and the reactionmixture was stirred at room temperature for 16 h. After completion(reaction monitored by TLC), the reaction mixture was quenched withwater and extracted with 25% IPA/DCM. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by using prep HPLC to afford the title compound(2.5 mg, 1%) as an off-white solid. TLC: 10% MeOH/DCM (Rf 0.5).(Analytical data in Table 1).

Synthetic Example 40

Synthesis of tert-butyl3-(((2-(((2-fluorophenyl)sulfonyl)carbamoyl)benzofuran-6-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate(69)

To a stirred solution of Compound 68 (203 mg, 0.94 mmol) in DMF (4 mL)at 0° C. was added DIPEA (0.443 mL, 2.58 mmol), followed by T₃P (410 mg,1.29 mmol). The contents were allowed to stir at room temperature for 20min. After, a pre-dissolved solution of Compound 32 (300 mg, 0.86 mmol)in DMF (0.5 mL) was added and the reaction mixture was stirred at roomtemperature for 12 h. After completion (reaction monitored by TLC), thereaction mixture was quenched with water and extracted with 10%MeOH/DCM. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to obtain the residue which wastriturated with di-ethyl ether/pentane to afford the title compound 69(220 mg, 47%) as an off-white solid. TLC: 10% MeOH/DCM (R_(f). 0.5);LCMS Calculated for C₂₆H₂₈FN₃O₇S: 545.58; Found: 547.01 (M+1).

Synthesis of N((2(((2fluorophenyl) sulfonyl) carbamoyl) benzofuran6yl)methyl) pyrrolidine-3-carboxamide hydrochloride (70)

To a stirred solution of compound 69 (200 mg, 0.36 mmol) in DCM (2 mL)at 0° C., 4N HCl in 1,4-dioxane (1 mL) was added and the reaction wasallowed to stir at room temperature for 1 h. After completion (reactionmonitored by TLC), the reaction mixture was concentrated under reducedpressure to obtain the residue, which was triturated with DCM/n-Heptaneto afford the title compound 70 (170 mg, HCl salt, 96%) as an off-whitesolid. TLC: 10% MeOH/DCM (R_(f). 0.3); LCMS Calculated forC₂₁H₂₀ClFN₃O₅S: 481.92; Found: 446.29 (Freebase M+1).

Synthesis of1-acryloyl-N-((2-(((2-fluorophenyl)sulfonyl)carbamoyl)benzofuran-6-yl)methyl)pyrrolidine-3-carboxamide

To a stirred solution of Compound 70 (120 mg, 0.25 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.13 mL, 0.76 mmol) and followed by T₃P (120mg, 0.39 mmol), acrylic acid (21 mg, 0.28 mmol). The reaction mixturewas stirred at room temperature for 16 h. After completion (reactionmonitored by TLC), the reaction mixture was quenched with cool water andextracted with 10% IPA/DCM. The organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to obtain the residue,which was purified by using prep HPLC to afford the title compound (4.7mg, 4%) as a brown solid. TLC: 10% MeOH/DCM (R_(f). 0.5). (Analyticaldata in Table 1).

Synthetic Examples 41 AND 42

Synthesis of tert-butyl2′-chloro-3,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate (72)

To a stirred solution of 4-bromo-2-chloropyridine 71 (3 g, 15.58 mmol)in 3:1 mixture of 1,4 dioxane: water (80 mL), was added K₂CO₃ (10.77 g,77.94 mmol) followed by Pd(PPh₃)₄ (0.9 g, 0.779 mmol) and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(5.78 g, 18.69 mmol). The resulting reaction mixture was stirred at 100°C. for 12 h. After completion (monitored by TLC), the reaction mixturewas cooled to room temperature, added water and extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by combi flash chromatography using a gradientmethod of 0-30% EtOAc/Heptane to afford the title compound 72 (2.8 g,61%) as a yellow solid. TLC: 50% EtOAc/Heptane (R_(f). 0.5). ¹H NMR (400MHz, DMSO-d₆): δ 8.35 (d, J=4.8 Hz, 1H), 7.52 (s, 1H), 7.47 (d, J=5.2Hz, 1H), 6.56 (brs, 1H), 4.03 (s, 2H), 3.54 (t, J=5.6 Hz, 2H), 2.46 (s,2H), 1.42 (s, 9H); LCMS Calculated for C₁₅H₁₉ClN₂O₂: 294.78; Found:294.97 (M+1).

Synthesis of tert-butyl2′-(3-(methoxycarbonyl)-5-methylphenyl)-3,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate(73)

To a stirred solution of compound 72 (1 g, 3.40 mmol) in a 3:1 mixtureof 1,4 dioxane: water (40 mL), was added K₂CO₃ (2.34 g, 17.00 mmol)followed by Pd(PPh₃)4 (196 mg, 0.17 mmol) and methyl3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.12g, 4.08 mmol). The reaction mixture was stirred at 90° C. for 12 h.After completion (reaction monitored by TLC), the reaction mixture wascooled to room temperature, added water and extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by combi flash chromatography using a gradientmethod of 0-30% EtOAc/Heptane to afford the title compound 73 (1.0 g,72%) as a pale yellow solid. TLC: 50% EtOAc/Heptane (R_(f). 0.5). ¹H NMR(400 MHz, DMSO-d₆): δ 8.63 (d, J=4.8 Hz, 1H), 8.53 (s, 1H), 8.25 (s,1H), 8.00 (s, 1H), 7.84 (s, 1H), 7.43 (q, J=2.1 Hz, 1H), 6.60 (brs, 1H),4.07 (s, 2H), 3.89 (s, 3H), 3.57 (t, J=5.2 Hz, 2H), 2.57-2.52 (m, 2H),2.47 (s, 3H), 1.40 (s, 9H); LCMS Calculated for C₂₄H₂₈N₂O₄: 408.50;Found: 409.0 (M+1).

Synthesis of tert-butyl4-(2-(3-(methoxycarbonyl)-5-methylphenyl)pyridin-4-yl)piperidine-1-carboxylate(74)

An autoclave was charged with a suspension of Compound 73 (700 mg, 1.7mmol) in EtOH (15 mL) and the mixture was purged with nitrogen for 5min. After, 10% Pd/C (350 mg) was added under nitrogen atmosphere. Thereaction mixture was purged with hydrogen gas and was allowed to stirunder hydrogen atmosphere (100 psi) at room temperature for 16 h. Theprogress of the reaction was monitored by TLC. After completion, thereaction mixture was filtered through a pad of Celite, and which waswashed with MeOH. The filtrate was concentrated under reduced pressureto the dryness. The crude product was purified by Combi flashchromatography using a gradient method of 0-5% MeOH/DCM to afford thedesired title compound 74 (600 mg, 85%) as white solid. TLC: 50%EtOAc/Heptane (Rf 0.6). LCMS Calculated for C₂₄H₃₀N₂O₄: 410.51; Found:411.08 (M+1).

Synthesis of tert-butyl4-(2-(3-(hydrazinecarbonyl)-5-methylphenyl)pyridin-4-yl)piperidine-1-carboxylate (75)

To a stirred solution of Compound 74 (1.0 g, 2.43 mmol) in EtOH (20 mL)was added hydrazine hydrate (6 mL) and the reaction was allowed to stirat 80° C. for 16 h. After completion (monitored by TLC), the reactionmixture was concentrated under reduced pressure to obtain the residuewhich was triturated with DCM/n-Heptane and concentrated under reducedpressure to afford the title compound 75 (600 mg, 60%) as a pale-yellowsolid. TLC: 5% MeOH/DCM (R_(f). 0.3). ¹H NMR (400 MHz, DMSO-d₆): δ 9.08(s, 1H), 8.55 (d, J=5.2 Hz, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.89 (s,1H), 7.68 (s, 1H), 7.26 (d, J=4.8 Hz, 1H), 4.49 (s, 2H), 3.10 (s, 1H),2.82-2.79 (m, 2H), 2.41 (s, 3H), 1.84-1.82 (m, 2H), 1.81 (s, 2H),1.62-1.58 (m, 2H), 1.43 (s, 9H); LCMS Calculated for C₂₃H₃₀N₄O₃: 410.52;Found: 409.01 (M−1).

Synthesis of tert-butyl 4-(2-(3-(2-((2-fluorophenyl)sulfonyl)hydrazine-1-carbonyl)-5-methylphenyl)pyridin-4-yl)piperidine-1-carboxylate(76)

To a stirred solution of compound 75 (300 mg, 0.73 mmol) in Pyridine (3mL) was added 2-fluorobenzenesulfonyl chloride (142 mg, 0.73 mmol) andthe reaction was allowed to stir at 80° C. for 16 h. After completion(reaction monitored by TLC), the reaction mixture was neutralized with1N HCl and extracted with ethyl acetate. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound 76 (230mg, Crude) as a brown solid. TLC: 5% MeOH/DCM (R_(f). 0.6); LCMSCalculated for C₂₉H₃₃FN₄O₅S: 568.66; Found: 569.86 (M+1).

Synthesis of2-fluoro-N′-(3-methyl-5-(4-(piperidin-4-yl)pyridin2yl)benzoyl)benzenesulfonohydrazide (77)

To a stirred solution of compound 76 (230 mg, 0.40 mmol) in DCM (3 mL)at 0° C., TFA (0.3 mL, 4.04 mmol) was added, and the reaction wasallowed to stir at room temperature for 1 h. After completion (reactionmonitored by TLC), the reaction mixture was concentrated under reducedpressure to afford the title compound 77 (180 mg, TFA salt) as a brownsolid. TLC: 5% MeOH/DCM (R_(f). 0.5). LCMS Calculated for C₂₆H₂₅F₄N₄O₄S:565.56; Found: 469.15 (Free base M+1).

Synthetic Example 41 Synthesis of N-(3-(4-(1-acryloylpiperidin-4-yl)pyridin-2-yl)-5-methylbenzoyl)-2-fluorobenzenesulfonohydrazide

To a stirred solution of 77 (60 mg, 0.11 mmol) in DCM (4 mL) at 0° C.was added Et₃N (0.04 mL, 0.30 mmol) followed by acryloyl chloride (8.1mg, 0.09 mmol). The reaction was stirred at the same temperature for 30min. After completion of the reaction (monitored by TLC), the reactionmixture was concentrated under reduced pressure. The crude compound waspurified using prep HPLC to afford the title compound (3.5 mg, 6.73%) asan off-white solid. TLC: 10% MeOH/DCM (R_(f). 0.5). (Analytical data inTable 1).

Synthetic Example 42 Synthesis of2-fluoro-N′-(3-methyl-5-(4-(1-(vinylsulfonyl)piperidin-4-yl)pyridin-2-yl)benzoyl)benzenesulfonohydrazide

To a stirred solution of compound 77 (200 mg, 0.35 mmol) in THF (5 mL)at 0° C. was added NaH [60% dispersion in mineral oil] (42 mg, 1.05mmol) and the contents were stirred for 15 min at the same temperature.After, ethenesulfonyl chloride (80 mg, 0.64 mmol) was added, and thereaction was allowed to stir at room temperature for 2 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasquenched with ice water and extracted with ethyl acetate. The combinedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by Prep-HPLC toafford the title compound (5 mg, 2.53%) as a white solid. TLC: 5%MeOH/DCM (R_(f). 0.2); (Analytical data in Table 1).

Synthetic Example 43

Synthesis of 4-bromo-2-cyclopropoxy-6-fluorobenzonitrile (79)

To a stirred solution of cyclopropanol (1.6 g, 27.64 mmol) in THF (50mL) at 0° C. was added a 1.0 M solution of LHMDS in THF (27.64 mL, 27.64mmol) and the contents were stirred at the same temperature for 1 h.After, a pre-dissolved solution of compound 78 (5 g, 23.04 mmol) in THF(5 mL) was added and the resulting reaction mixture was slowly allowedto stir at room temperature for 16 h. After completion of the reaction(monitored by TLC), reaction mixture was quenched with saturated NH₄Clsolution and extracted with ethyl acetate. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified bycombi-flash chromatography using a gradient method of 40-70%EtOAc/Heptane to afford the title compound 79 (2.5 g, 42.37%) as apale-yellow liquid. TLC: 30% EtOAc/Heptane (R_(f). 0.4). ¹H NMR (400MHz, DMSO-d₆): δ 7.57 (s, 1H), 7.54 (d, J=8.8 Hz, 1H), 4.19-4.16 (m,1H), 0.91-086 (m, 2H), 0.85-0.79 (m, 2H); LCMS Calculated forC₁₀H₇BrFNO: 256.07; Found: 256.1 (M+1).

Synthesis of methyl 4-cyano-3-cyclopropoxy-5-fluorobenzoate (80)

To an argon purged solution of Compound 79 (2.8 g, 10.93 mmol) in MeOH(70 mL) was added TEA (4.73 mL, 32.80 mmol), followed by Pd(OAC)₂ (0.122g, 0.54 mmol) and 1,3-bis(diphenylphosphino)propane (0.45 g, 1.09 mmol).The reaction was purged again with argon for 15 min. After, theresulting reaction mixture was filled with CO (g) and the reaction wasallowed to stir in a steel bomb at 80° C. for 16 h. The progress of thereaction was monitored by TLC. After completion, the reaction mixturewas filtered through a pad of Celite and which was washed with ethylacetate. The filtrate was concentrated under reduced pressure. The crudecompound was purified by combi-flash chromatography using a gradientmethod of 10-40% EtOAc/Heptane to afford the title compound 80 (1.76 g,68.71%) as a pale-yellow liquid. TLC: 50% EtOAc/Heptane (R_(f). 0.4); ¹HNMR (400 MHz, DMSO-d₆): δ 7.78 (s, 1H), 7.57 (d, J=9.2 Hz, 1H),4.72-4.60 (m, 1H), 3.92 (s, 3H), 0.91 (d, J=5.2 Hz, 2H), 0.81 (s, 2H);LCMS Calculated for C₁₂H₁₀FNO₃: 235.21; Found: 236.40 (M+1).

Synthesis of 2-cyclopropoxy-6-fluoro-4-(hydroxymethyl)benzonitrile (81)

To a stirred solution of compound 80 (2 g, 8.50 mmol) in THF (20 mL) atroom temperature was added LiBH₄ (0.56 g, 25.50 mmol) and the resultingreaction mixture was stirred at 60° C. for 4 h. After completion(reaction monitored by TLC), the reaction mixture was quenched with icewater and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford the title compound 81 (1.5 g, crude) as anoff white solid. TLC: 30% EtOAc/Heptane (R_(f). 0.35). ¹H NMR (400 MHz,DMSO-d₆): δ 7.31 (s, 1H), 7.01 (d, J=10.0 Hz, 1H), 5.61-5.52 (m, 1H),4.59 (d, J=5.2 Hz, 2H), 4.06 (s, 1H), 0.87 (d, J=6.0 Hz, 2H), 0.77 (s,2H); LCMS Calculated for C₁₁H₁₀FNO₂: 207.20; Found: 208.2 (M+1).

Synthesis of 4-(bromomethyl)-2-cyclopropoxy-6-fluorobenzonitrile (82)

To a stirred solution of compound 81 (1.5 g, 7.23 mmol) in ACN (15 mL)at 0° C. was added PPh₃ (3.03 g, 11.58 mmol), followed by Br₂ (0.61 mL,12.00 mmol) and the resulting reaction mixture was stirred at 60° C. for3 h. After completion (reaction monitored by TLC), the mixture wasquenched with ice water and extracted with ethyl acetate. The organiclayer was collected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycombi-flash chromatography using a gradient method of 20-30%EtOAc/Heptane to afford the title compound 82 (1.5 g, 76.9%) as an offwhite solid. TLC: 50% EtOAc/Heptane (R_(f). 0.45). ¹H NMR (400 MHz,DMSO-d₆): δ 7.46 (s, 1H), 7.23 (d, J=10.0 Hz, 1H), 4.74 (s, 2H),3.61-3.52 (m, 1H), 0.89 (d, J=6.0 Hz, 2H), 0.78 (s, 2H); LCMS Calculatedfor C₁₁H₉BrFNO: 270.10; Found: 269.7 (M−1).

Synthesis of tert-butyl((1-(4-cyano-3-cyclopropoxy-5-fluorobenzyl)-1H-pyrazol-4-yl)methyl)carbamate (83)

To a stirred solution of compound 82 (1.5 g, 5.55 mmol) in 1,4-Dioxane(15 mL) at room temperature was added DIPEA (1.93 mL, 11.10 mmol),followed by tert-butyl ((1H-pyrazol-4-yl)methyl)carbamate (1.2 g, 6.10mmol) and the resulting reaction mixture was heated at 60° C. for 16 h.After completion (reaction monitored by TLC), the reaction mixture wascooled to room temperature, water added and extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by Combi-flash chromatography using a gradientmethod of 30-40% EtOAc/Heptane to afford the title compound 83 (1.25 g,58.41%) as a yellow gummy-solid. TLC: 50% EtOAc/Heptane (R_(f). 0.5). ¹HNMR (400 MHz, DMSO-d₆): δ 7.72 (s, 1H), 7.40 (s, 1H), 7.16-7.13 (m, 2H),6.75 (d, J=10.0 Hz, 1H), 5.41 (s, 2H), 4.05 (s, 2H), 4.00-3.96 (m, 1H),1.37 (s, 9H), 0.84 (d, J=5.6 Hz, 2H), 0.74 (s, 2H); LCMS Calculated forC₂₀H₂₃FN₄O₃: 386.43; Found: 387.43 (M+1).

Synthesis of tert-butyl((1-((3-amino-4-cyclopropoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(84)

To a stirred solution of compound 83 (1.1 g, 2.84 mmol) in a 6:1 mixtureof DMF: H₂O (7 mL) at room temperature was added N-hydroxy acetamide(0.64 g, 8.54 mmol) and followed by K₂CO₃ (1.97 g, 14.23 mmol). Thereaction mixture was allowed to stir at 70° C. for 16 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wascooled to room temperature, ice water added and extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by Combi flash chromatography using a gradientmethod of 50-60% EtOAc/Heptane to afford the title compound 84 (0.90 g,79.64%) as a brown semi-solid. TLC: 80% EtOAc/Heptane (R_(f). 0.30). ¹HNMR (400 MHz, DMSO-d₆): δ 7.68 (s, 1H), 7.36 (s, 1H), 7.14 (br s, 1H),6.85 (s, 1H), 6.71 (s, 1H), 5.82 (s, 2H), 5.37 (s, 2H), 4.05-4.00 (m,1H), 3.96-3.92 (m, 2H), 1.36 (s, 9H), 0.81 (d, J=4.0 Hz, 4H); LCMSCalculated for C₂₀H₂₅N₅O₄: 399.45; Found: 400.02 (M+1).

Synthesis of tertbutyl((1((4cyclopropoxy3((2methoxyphenyl) sulfonamido)benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl)carbamate (85)

To a stirred solution of compound 84 (0.3 g, 0.75 mmol) in THF (5 mL) at0° C. was added 1.0 M solution of KO^(t)Bu in THF (2.25 mL, 2.25 mmol)followed by 2-methoxybenzenesulfonyl chloride (0.31 g, 1.50 mmol) andthe reaction was allowed to stir at room temperature for 16 h. Aftercompletion of the reaction (monitored by TLC), the mixture was dilutedwith ethyl acetate, water added and extracted. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byCombi flash column chromatography using a gradient method of 40-60%EtOAc/Heptane to afford the title compound 85 (0.180 g, 42.55%) as anoff white solid. TLC: 70% EtOAc (R_(f). 0.5). ¹H NMR (400 MHz, DMSO-d₆):δ 10.11 (s, 1H), 7.81-7.79 (d, J=6.8, Hz, 1H), 7.67 (s, 1H), 7.62 (br s,2H), 7.36 (s, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.10 (t, J=7.2 Hz, 1H), 6.94(s, 1H), 6.88 (s, 1H), 5.41 (s, 2H), 3.96 (d, J=5.6 Hz, 2H), 3.67 (s,3H), 1.36 (s, 9H), 0.78 (d, J=5.6 Hz, 2H), 0.63 (s, 2H); LCMS Calculatedfor C₂₇H₃₁N₅O₇S: 569.63; Found: 570.8 (M+1).

Synthesis ofN-(4-cyclopropoxy-6-((4-(((2,2,2-trifluoroacetyl)-14-azaneyl)methyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide(86)

To a stirred solution of compound 85 (0.15 g, 0.26 mmol) in DCM (3 mL)at 0° C., TFA (0.2 mL, 2.63 mmol) was added and the reaction was allowedto stir at room temperature for 2 h. After completion of the reaction(monitored by TLC), the mixture was concentrated under reduced pressureto get the residue, which was washed with diethyl ether/heptane toafford the title compound 86 (0.1 g, 80.8%) as a brown gummy solid. TLC:10% MeOH/DCM (R_(f). 0.5). LCMS Calculated for C₂₂H₂₃N₅O₅S: 469.52;Found: 470.4 (M+1).

Synthesis ofN-((1-((4-cyclopropoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide

To a stirred solution of compound 86 (100 mg, 0.21 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.1 mL, 0.63 mmol), followed by T₃P (87 mg,0.27 mmol) and the contents were allowed to stir at room temperature for20 min. After that, a pre-dissolved solution of propiolic acid (17.6 mg,0.25 mmol) in DMF (0.3 mL) was added in a drop-wise manner and thereaction was allowed to stir at room temperature for 4 h. Aftercompletion (reaction monitored by TLC), the reaction mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas collected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byusing prep. HPLC to afford the title compound (5 mg, 4.5%) as an offwhite solid. TLC: 10% MeOH/DCM (R_(f). 0.5). (Analytical data in Table1).

Synthetic Example 44

Synthesis of 4-(bromomethyl)-2-fluoro-6-methoxybenzonitrile (87)

To a stirred solution of2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile 15 (3 g, 16.54 mmol) inACN (15 mL) at 0° C. was added PPh₃ (6.94 g, 26.46 mmol) followed by Br₂(1.34 mL, 26.46 mmol). The reaction was stirred at 60° C. for 3 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice water and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by combi-flash chromatographyusing a gradient method of 20-30% EtOAc/Heptane to afford the titlecompound 87 (3 g, 74.62%) as a brown solid. TLC: 50% EtOAc/Heptane (Rf:0.45). LCMS Calculated for C9H7BrFNO: 242.97; Found: 244.7 (M+2).

Synthesis of tert-butyl (3aR,6aS)-5-(4-cyano-3-fluoro-5-methoxybenzyl)hexahydropyrrolo[3,4-c] pyrrole-2(1H)-carboxylate (88)

To a stirred solution of 4-(bromomethyl)-2-fluoro-6-methoxybenzonitrile87 (0.5 g, 2.048 mmol) in DMF (5 mL) at room temperature was addedtert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c] pyrrole-2(1H)-carboxylate87 (0.478 g, 2.25 mmol) followed by DIPEA (1.14 mL, 4.09 mmol). Thereaction mixture was allowed to stir at 70° C. for 16 h. Aftercompletion f the reaction (monitored by TLC), the reaction mixture wascooled to room temperature, quenched with ice water and extracted withethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound 88(0.550 g, 71.52%) as an off-white solid. TLC: 90% EtOAc/Heptane (Rf:0.40). ¹H NMR is complicated and indicates a regioisomeric mixture. LCMSCalculated for C20H26FN3O3: 375.20; Found: 376.42 (M+1)

Synthesis of tert-butyl(3aR,6aS)-5-((3-amino-4-methoxybenzo[d]isoxazol-6-yl) methyl)hexahydropyrrolo[3,4-c] pyrrole-2(1H)-carboxylate (89)

To a stirred solution of compound of tert-butyl(3aR,6aS)-5-(4-cyano-3-fluoro-5-methoxybenzyl) hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate 88 (0.85 g, 2.26 mmol) in a mixture of DMF:H₂O (20 mL, 18:2) at room temperature was added N-hydroxy acetamide (0.4g, 6.79 mmol) and followed by K₂CO₃ (1.87 g, 13.56 mmol). The reactionmixture was allowed to stir at 60° C. for 16 h. After completion of thereaction (monitored by TLC), the reaction mixture was cooled to roomtemperature, quenched with water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycombi flash chromatography (230-400 mesh silica) using a gradient methodof 1-5% MeOH in DCM to afford the title compound 89 (800 mg, 92%) as abrown semi-solid. TLC: 5% MeOH/DCM (Rf: 0.40). LCMS Calculated forC20H28N4O4: 388.21; Found: 389.4 (M+1)

Synthesis of tert-butyl (3aR,6aS)-5-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl) hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (90)

To a stirred solution of tert-butyl(3aR,6aS)-5-((3-amino-4-methoxybenzo[d]isoxazol-6-yl) methyl)hexahydropyrrolo[3,4-c] pyrrole-2(1H)-carboxylate 89 (0.15 g, 0.386mmol) in THF (1.5 mL) at the room temperature was added tBuONa (0.186 g,1.93 mmol) and stirred for 15 min. followed by addition of3-methoxybenzenesulfonyl chloride (0.159 g, 0.772 mmol). The reactionwas allowed to stir at 50° C. for 16 h. After completion of the reaction(monitored by TLC), the reaction mixture was concentrated under reducedpressure. The crude compound was purified by over combi flashchromatography using a gradient of 5% Methanol/DCM/Heptane to afford thetitle compound 90 (0.2 g, 93.02%) as a pale-yellow solid. TLC:EtOAc/Heptane (Rf: 0.50). LCMS Calculated for C27H34N4O7S: 558.21;Found: 559.02 (M+1)

Synthesis of N-(6-(((3aR,6aS)-hexahydropyrrolo[3,4-c] pyrrol-2(1H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride (91)

To a stirred solution of tert-butyl(3aR,6aS)-5-((4-methoxy-3-((2-methoxyphenyl) sulfonamido)benzo[d]isoxazol-6-yl) methyl) hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate 90 (0.8 g, 1.43 mmol) in DCM (5 mL) at 0° C.was added 4M HCl in 1,4-dioxane (5 mL). The reaction was allowed to stirat the room temperature for 3 h. After completion of the reaction(monitored by TLC), the reaction mixture was concentrated under reducedpressure to afford the title compound 91 (0.690 g, 97.45%, HCl salt) asan off-white solid. TLC: 10% MeOH/DCM (Rf: 0.5). LCMS Calculated forC22H27ClN4O5S: 494.14; Found: NA (M+1). Salt was taken forward for thenext step without any further purification.

Synthesis of2-methoxy-N-(4-methoxy-6-(((3aR,6aS)-5-propioloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of N-(6-(((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride 91 (0.2 g, 0.404 mmol) in DMF (1 mL) at 0° C. was addedDIPEA (0.176 mL, 1.01 mmol), T₃P (0.192 g, 0.606 mmol) followed bypropiolic acid (56 mg, 0.808 mmol). The reaction was allowed to stir atthe room temperature for 4 h. After completion (reaction monitored byTLC), the reaction mixture was concentrated under reduced pressure toget brown gummy solid. The crude was purified through combi-flashchromatography using gradient 5%-10% to get compound which is furtherpurified by prep HPLC to afford the title compound (55 mg, 26.6%) as anoff-white solid. TLC: 10% MeOH/DCM (Rf: 0.40). (See Table 1 foranalytical data).

Synthetic Example 45

Synthesis of tert-butyl((1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazol-4-yl)methyl)(methyl)carbamate(92)

To a stirred solution of 4-(bromomethyl)-2-fluoro-6-methoxybenzonitrile87 (1.2 g, 4.916 mmol) in DMF (12 mL) at room temperature was addedDIPEA (2.57 mL, 14.75 mmol) and allowed to stir for 10 min. followed byaddition tert-butyl ((1H-pyrazol-4-yl) methyl) (methyl) carbamate 97(1.2 g, 5.89 mmol). The reaction mixture was stirred at 70° C. for 16 h.After completion of the reaction (monitored by TLC), the reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycombi-flash chromatography (100-200 mesh) using gradient method of 0-50%EtOAc/Heptane to offer the title compound 92 (0.6 g, 33.33%) as a gummySolid. TLC: 50% EtOAc/Heptane (R_(f). 0.30) LCMS Calculated forC₁₉H₂₃FN₄O₃: 374.18; Found:375.3.

Synthesis of tert-butyl ((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl) methyl) (methyl)carbamate (93)

To a stirred solution of tert-butyl((1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazol-4-yl) methyl) (methyl)carbamate 92 (0.5 g, 1.33 mmol) in solution of DMF: H₂O (5 mL, 5:1) atroom temperature was added N-hydroxyl acetamide (0.35 g, 3.99 mmol) andK₂CO₃ (1.1 g, 7.98 mmol). The reaction mixture was allowed to stir at70° C. for 16 h. After completion of the reaction (monitored by TLC),the reaction mixture was cooled to room temperature, diluted with waterand ethyl acetate, and extracted with ethyl acetate. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto afford the tert-butyl ((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl) methyl) (methyl)carbamate 93 (0.4 g, 77.36%) asa brown semi-solid. TLC: 50% EtOAc/Heptane (Rf: 0.20). LCMS Calculatedfor C₁₉H₂₅N₅O₄: 387.19; Found: 388.4 (M+1).

Synthesis of tert-butyl ((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl)(methyl)carbamate (94)

To a stirred solution of tert-butyl((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl) (methyl)carbamate 93 (0.33 g, 0.851 mmol) in THF (3 mL) at 0° C.was added 1.0 M solution of KOtBu (3.4 mL, 3.406 mmol) in THF followedby 2-methoxybenzenesulfonyl chloride (386 mg, 1.87 mmol). The reactionwas allowed to stir at room temperature for 16 h. After completion ofthe reaction (monitored by TLC), the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by Combi flash (100-200 mesh) columnchromatography using a gradient method of 100% EtOAc/Heptane to affordthe title compound 94 (0.130 g, 27.42%) as an off-white solid. TLC: 70%EtOAc (Rf: 0.5). LCMS Calculated for C26H31N5O7S: 557.19; Found: 558.5(M+1).

2,2,2-trifluoro-N-((1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido)benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl)-N-methylacetamide (95)

To a stirred solution of tert-butyl ((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl)(methyl)carbamate 94 (13 mg, 0.233 mmol) in DCM (5 mL) at 0° C., wasadded TFA (0.52 mL,). The reaction was allowed to stirred at the roomtemperature for 4 h. After completion of the reaction (monitored byTLC), the reaction mixture was concentrated under reduced pressure toafford the title compound 95 (100 mg, 94%) as a brown gummy solid. TLC:10% MeOH/DCM (Rf: 0.5). LCMS Calculated for C23H22F3N₅O₆S: 553.12;Found: 458.0 (M+1). This was taken forward for the next step without anyfurther purification.

Synthesis of N-((1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido)benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl)-N-methylpropiolamide

To a stirred solution of2,2,2-trifluoro-N-((1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido)benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl)-N-methylacetamide 95 (90 mg, 0.162 mmol) in DMF (1 mL) at 0° C.was added DIPEA (0.08 mL, 0.487 mmol), T₃P 50% solution in EtOAc (77 mg,0.243 mmol). The reaction was allowed to stir at the room temperaturefor 15 min. After that, a pre-dissolved solution of propiolic acid (13.6mg, 0.194 mmol) in DMF (0.5 mL) was added dropwise. The reaction wasallowed to stir at the room temperature for 4 h. After completion(monitored by TLC), the reaction mixture was quenched with water andextracted with ethyl acetate. The organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by using prep HPLC to afford the title compound (39 mg, 85%) asan off-white solid. TLC: 10% MeOH/DCM (Rf: 0.5). (See analytical datafor Table 1). TLC: 10% MeOH/DCM (Rf: 0.4). LCMS Calculated forC24H23N5O6S: 509.14; Found: 510.1 (M+1) (See Table 1 for analyticaldata).

Synthesis of tert-butyl ((1H-pyrazol-4-yl)methyl)(methyl)carbamate (97)

To a stirred solution of N-methyl-1H-pyrazole-4-carboxamide 96 (2 g,15.98 mmol) in DMF (10 mL) at −10° C. was added LAH (1.5 g, 39.95 mmol).The reaction was allowed to stir at the 80° C. for 16 h. Aftercompletion of reaction (monitored by TLC), the reaction mixture wasquenched with 20% NaOH (100 mL) and diluted with DCM (20 mL). Theorganic layer was collected and (Boc)₂O (2.78 mL, 12.78 mmol) was addeddropwise and the mixture was stirred at room temperature for 2 h. Aftercompletion of reaction (monitored by TLC) the mixture was concentratedunder reduced pressure. The crude compound was purified by Combi flashchromatography (230-400 mesh) to afford the title compound 97 (1.2 g,35.6%) TLC: 20% EA/Heptane (Rf: 0.3). LCMS Calculated for C₁₀H₁₇N₃O₂:211.13; Found: 212.60 (M+1).

Synthetic Example 46

Methyl 4-(N-(6-((4-(((tert-butoxycarbonyl) amino)methyl)-1H-pyrazol-1-yl) methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-3-methoxybenzoate (98)

To a stirred solution of tert-butyl((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate22 (200 mg, 0.535 mmol) in THF (3 mL) was added NaOtBu (154 mg, 1.605mmol) followed by methyl 4-(chlorosulfonyl)-3-methoxybenzoate (283 mg,1.07 mmol). The reaction mixture was allowed to stir at the roomtemperature for 2 h. After completion (monitored by TLC), the reactionmixture was quenched with ice water then extracted with ethyl acetate.The organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by combi flashchromatography (neutral alumina) to afford the title compound 98 (92 mg,28.57%), yellow solid. TLC: 100 EtOAc (Rf: 0.6). LCMS Calculated forC27H31N5O9S:601.18; Found:602.5 (M+1).

Synthesis of4-(N-(6-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-3-methoxybenzoicacid (99)

To a stirred solution of methyl4-(N-(6-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-3-methoxybenzoate98 (80 mg, 0.132 mmol) in solution of THF-H₂O (1.6 mL, 1:1) was addedLiOH·H₂O (13.96 mg, 0.332 mmol). The reaction mixture was stirred at theroom temperature for 2 h. After completion (reaction monitored by TLC),the reaction mixture was diluted with water and washed with ethylacetate. The aqueous layer was neutralized with 1N HCl (pH=5) andextracted with 10% MeOH/DCM. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford the crude title compound 99 (70 mg, 89.74%) as a gummy solid.TLC: 10% MeOH/DCM (Rf: 0.2) LCMS Calculated for C26H29N5O9S: 587.17;Found:589.08 (M+1).

Synthesis of tert-butyl((1-((4-methoxy-3-((2-methoxy-4-(methylcarbamoyl) phenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(100)

To a stirred solution of 4-(N-(6-((4-(((tert-butoxycarbonyl) amino)methyl)-1H-pyrazol-1-yl) methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-3-methoxybenzoic acid 99 (60 mg, 0.1021 mmol) in DMF (2 mL)at 0° C. was added methylamine hydrochloride (10.34 mg, 0.153 mmol),DIPEA (0.071 mL, 0.408 mmol), followed by T₃P 50% solution in EtOAc(0.129 mL, 0.204 mmol). The reaction was allowed to stir at the roomtemperature for 3 h. After completion (reaction monitored by TLC), thereaction mixture was quenched with ice-water and extracted with ethylacetate. The organic layer was dried over anhydrous Na₂SO₄, concentratedunder reduced pressure to afford the crude compound 100 (70 mg, crude)as a white solid. TLC: 10% MeOH/DCM (R_(f). 0.5). LCMS Calculated forC27H32N6O8S: 600.20; Found: 601.8 (M+1) The crude compound used for nextreaction without any purification.

Synthesis of 4-(N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-3-methoxy-N-methylbenzamidehydrochloride (101)

To a stirred solution of tert-butyl((1-((4-methoxy-3-((2-methoxy-4-(methylcarbamoyl) phenyl) sulfonamido)benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) carbamate 100(70 mg, 0.1165 mmol) in DCM (1 mL) at 0° C. was added TFA (0.094 mL,1.165 mmol). The reaction was allowed to stir at the room temperaturefor 2 h. After completion (reaction monitored by TLC), the reactionmixture was concentrated under reduced pressure and co distilled withtoluene to afford the title compound 101 (72 mg, crude,) as a brown oil.TLC: 10% MeOH/DCM (Rf: 0.3). LCMS Calculated for C22H25ClN6O6S: 536.12:Found: 501.50 (M+1).

Synthesis of3-methoxy-4-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl) benzo[d]isoxazol-3-yl) sulfamoyl)-N-methylbenzamide

To a stirred solution of4-(N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-3-methoxy-N-methylbenzamidehydrochloride 101 (50 mg, 0.093 mmol) in DMF (1 mL) at 0° C. was addedpropiolic acid (7.8 mg, 0.111 mmol) followed by DIPEA (0.064 mL, 0.372mmol). The reaction was allowed to stir at the room temperature for 10min and T₃P (44 mg, 0.139 mmol) was added. The reaction was allowed tostir at the room temperature for 3 h. After completion (monitored byTLC), the reaction mixture was quenched with ice water and extractedwith ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude compound was purifiedby using prep HPLC to afford the title compound (7 mg, 13.7%) as anoff-white solid, TLC: 10% MeOH/DCM (Rf: 05). (See Table 1 for analyticaldata)

Synthetic Example 47

Synthesis of N-((1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)-N-methylacrylamide

To a stirred solution of2-methoxy-N-(4-methoxy-6-((4-((methyl(2,2,2-trifluoroacetyl)-14-azaneyl)methyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide95 (0.100 g, 0.180 mmol) in DMF (1 mL) at 0° C. was added DIPEA (0.094mL, 0.54 mmol) and T₃P 50% solution in EtOAc (0.114 mL, 0.270 mmol). Thereaction was allowed to stir at the room temperature for 10 min.followed by addition of a pre-dissolved solution of acrylic acid (25 mg,0.360 mmol) in DMF (0.3 mL) dropwise. The reaction was allowed to stirat the room temperature for 4 h. After completion (reaction monitored byTLC), the reaction mixture was concentrated under reduced pressure. Thecrude compound was purified by using prep HPLC to afford the titlecompound (32 mg, 34.78%) as an off-white solid. TLC: 10% MeOH/DCM (Rf:0.5). (See analytical data for Table 1)

Synthetic Example 48

Synthesis of tert-butyl(1-(4-cyano-3-fluoro-5-methoxybenzyl)pyrrolidin-3-yl)carbamate (103)

To a stirred solution of 4-(bromomethyl)-2-fluoro-6-methoxybenzonitrile87 (1.5 g, 6.14 mmol) in DMF (10 mL) at room temperature was added DIPEA(2.14 mL, 12.28 mmol), followed by tert-butyl pyrrolidin-3-ylcarbamate(1.25 g, 6.76 mmol). The reaction was heated at 60° C. for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was cooled to roomtemperature, ice cold water added and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound 103(1g, 46.72%) as a yellow solid. TLC: 100% EtOAc (Rf: 0.5). LCMSCalculated for C18H24FN3O3: 349.18; Found: 350.4 (M+1).

Synthesis of tert-butyl(1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)pyrrolidin-3-yl)carbamate(104)

To a stirred solution of tert-butyl(1-(4-cyano-3-fluoro-5-methoxybenzyl) pyrrolidin-3-yl) carbamate 103 (1g, 2.86 mmol) in DMF: H₂O (7 mL, 6:1) at room temperature was addedN-hydroxy acetamide (0.644 g, 8.59 mmol) and followed by K₂CO₃ (2.37 g,17.16 mmol). The reaction mixture was allowed to stir at 70° C. for 16h. After completion (monitored by TLC), the reaction mixture was pouredon ice water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by Combi flashchromatography using a gradient method of 70% EtOAc/heptane to affordthe title compound 104 (600 mg, 58.25%) as a brown semi-solid. TLC: 100%EtOAc (Rf: 0.50); LCMS Calculated for C18H26N4O4: 362.20; Found: 363.02(M+1).

Synthesis of tert-butyl (1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido)benzo[d]isoxazol-6-yl) methyl) pyrrolidin-3-yl) carbamate (105)

To a stirred solution of tert-butyl(1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl) methyl)pyrrolidin-3-yl)carbamate 104 (0.6 g, 1.65 mmol) in THF (6 mL) at 0° C.was added KOtBu 1M solution in THF (5.0 mL, 4.96 mmol) followed by3-methoxybenzenesulfonyl chloride (0.681 g, 3.31 mmol). The reaction wasallowed to stir at room temperature for 16 h. After completion(monitored by TLC), the reaction mixture was quenched with saturatedammonium chloride solution and extracted with ethyl acetate. Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude compound was purified byusing combi flash chromatography (230-400 mesh) using a gradient of70-80% ethyl acetate/heptane to afford the title compound 105 (300 mg,34.09%) as a white solid. TLC: 10% MeOH/DCM (Rf. 0.5); LCMS Calculatedfor C25H32N4O7S:532.20: Found:533.02 (M+1)

Synthesis ofN-(6-((3-aminopyrrolidin-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride (106)

To a stirred solution of tert-butyl (1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl) pyrrolidin-3-yl) carbamate105 (0.3 g, 0.563 mmol) in DCM (3 mL) at 0° C. was added 4M HCl in1,4-Dioxane (3 mL). The reaction was allowed to stir at the roomtemperature for 2 h. After completion (monitored by TLC), the reactionmixture was concentrated under reduced pressure. The crude product waswashed with diethyl ether and heptane to afford the title compound 106(250 mg, salt) as a pale brown semi solid. TLC: 10% MeOH/DCM (Rf: 0.5).LCMS Calculated for C₂₂H₂₄F₃N₄O₆S: 529.14; Found: 432.08 (Freebase+1).

Synthesis ofN-(1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)pyrrolidin-3-yl)propiolamide

To a stirred solution ofN-(6-((3-aminopyrrolidin-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride 106 (35 mg, 0.066 mmol) in DMF (1 mL) at 0° C. was addedDIPEA (0.034 mL, 0.198 mmol), T₃P 50% solution in EtOAc (0.062 mL, 0.099mmol) followed by propiolic acid (9.2 mg, 0.132 mmol). The reaction wasallowed to stir at the room temperature for 1 h. After completion(reaction monitored by TLC), the reaction mixture was concentrated underreduced pressure, quenched with ice water, and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The crude was purifiedby prep HPLC to afford the title compound (5 mg, 15.62%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.6). (See Table 1 for analytical data).

Synthetic Example 49

Synthesis of tert-butyl(1-(4-cyano-3-fluoro-5-methoxybenzyl)piperidin-4-yl)carbamate (107)

To a stirred solution of 4-(bromomethyl)-2-fluoro-6-methoxybenzonitrile87 (1 g, 4.09 mmol) in DMF (10 mL) at 0° C. was added tert-butylpiperidin-4-ylcarbamate (0.984 g, 4.915) and DIPEA (2.14 mL, 12.27mmol). The reaction mixture was allowed to stir at the room temperaturefor 16 h. After completion (monitored by TLC), the reaction mixture wasquenched with ice cold water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The crude compound was purified byusing combi flash chromatography using a gradient method of 20-40%EtOAc/Heptane to afford the title compound 107 (850 mg, 57.43%) as apale-yellow solid. TLC: 70% EtOAc/Pentane (Rf: 0.4): LCMS Calculated forC19H26FN3O3: 363.20; Found: 364.0 (M+1).

Synthesis of tert-butyl (1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)piperidin-4-yl)carbamate (108)

To a stirred solution of compound tert-butyl(1-(4-cyano-3-fluoro-5-methoxybenzyl) piperidin-4-yl) carbamate 107 (0.3g, 0.825 mmol) in solution of DMF: H₂O (10.5 mL, 6:1) at roomtemperature was added K₂CO₃ (0.684 g, 4.95 mmol). The mixture wasallowed to stir for 10 min followed by addition of N-hydroxyl acetamide(0.185 g, 2.475 mmol). The mixture was allowed to stir at 70° C. for 16h. After completion (monitored by TLC), the reaction mixture was cooledto room temperature, diluted with water, and extracted with ethylacetate. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byusing combi flash chromatography using a gradient method of 10-70%EtOAc/Heptane to afford the title compound 108 (290 mg, 93.54%) as abrown semi-solid. TLC: 80% EtOAc/Heptane (R_(f). 0.50); LCMS Calculatedfor C₁₉H₂₈N₄O₄: 376.21; Found: 377.4 (M+1).

Synthesis of tert-butyl (1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido)benzo[d]isoxazol-6-yl) methyl) piperidin-4-yl) carbamate (109)

To a stirred solution of compound tert-butyl(1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl) methyl) piperidin-4-yl)carbamate 108 (0.5 g, 1.328 mmol) in THF (5 mL) at 0° C. was added KOtBu1.0 M in THF (3.98 mL, 3.98 mmol) followed by 2-methoxybenzenesulfonylchloride (0.548 g, 2.656 mmol). The reaction was allowed to stir at roomtemperature for 16 h. After completion (monitored by TLC), the reactionmixture was quenched with water and extracted ethyl acetate. The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude compound was purified by Combi flash column chromatography using agradient method of 0-5% MeOH/DCM to afford the title compound 109 (0.250g, 34.4%) as a white solid. TLC: 70% EtOAc/Pentane (Rf: 0.45); LCMSCalculated for C26H34N4O7S: 546.21; Found: 547.5 (M+1).

Synthesis of N (6((4aminopiperidinlyl)methyl)4methoxybenzo[d]isoxazol3yl)2methoxybenzenesulfonamidehydrochloride (110)

To a stirred solution of compound tert-butyl(1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido) benzo[d]isoxazol-6-yl)methyl) piperidin-4-yl) carbamate 109 (0.250 g, 0.4573 mmol) in DCM (5mL) at 0° C. was added 4M HCl in 1,4-Dioxane (2.5 mL). The reaction wasallowed to stir at the room temperature for 4 h. After completion(reaction monitored by TLC), the reaction mixture was concentrated underreduced pressure to afford the title compound 110 (240 mg, 100%) as.TLC: 10% MeOH/DCM (Rf: 0.5). LCMS Calculated for C₂₁H₂₇ClN₄O₅S; 482.14;Found: 447.0 (Freebase+1).

Synthesis ofN-(1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)piperidin-4-yl)acrylamide

To a stirred solution of N-(6-((4-aminopiperidin-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride 110 (0.100 mg, 0.207 mmol) in DCM (4 mL) at 0° C. wasadded TEA (0.087 mL, 0.621 mmol) and acryloyl chloride (15 mg, 0.207mmol). The resulting reaction mixture was allowed to stir at 0° C. for 2h. After completion (monitored by TLC), the reaction mixture wasquenched with water and extracted with DCM. The organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by prep HPLC to afford the title compound (15 mg,13.3%) as an off-white solid. TLC: 10% MeOH/DCM (Rf: 0.5). LCMSCalculated for C24H28N4O6S: 500.17; Found: 501.5 (M+1). (See Table 1 foranalytical data)

Synthetic Example 50

Synthesis ofN-(6-(((3aR,6aS)-5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide

To a stirred solution of N-(6-(((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride 91 (0.1 g, 0.202 mmol) in DMF (1 mL) at 0° C. was addedTEA (0.0425 mL, 0.303 mmol) and acryloyl chloride (20 mg, 0.222 mmol).The reaction was allowed to stir at the room temperature for 4 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure to get a brown gummy product. The crude waspurified over combi-flash chromatography using gradient 5-10% MeOH inDCM and further purified by prep HPLC to afford the title compound (8.5mg, 8.09%) as an off white solid. TLC: 10% MeOH/DCM (Rf: 0.40). (Seeanalytical data for Table 1).

Synthetic Example 51

Synthesis ofN-((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)acrylamide

To a stirred solution ofN-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride 56 (60 mg, 0.125 mmol) in DCM (2 mL) at 0° C. was addedTEA (0.05 mL, 0.375 mmol) and a solution of acryloyl chloride (11 mg,0.125 mmol) in DCM (0.6 mL). The reaction mixture was allowed to stir atthe 0° C. for 4 h. After completion (monitored by TLC), the reactionmixture was quenched with water and extracted with DCM. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude was purified by prep HPLC to afford the titlecompound (8 mg, 12.90%) as an off-white solid. TLC: 10% MeOH/DCM (Rf:0.5). (See Table 1 for analytical data).

Synthetic Example 52

Synthesis of 3-(N-(6-((4-(aminomethyl)-1Hpyrazol1yl)methyl)4methoxybenzo[d]isoxazol-3-yl) sulfamoyl)-N-methyl benzamide(111)

To a stirred solution of tert-butyl((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate22 (100 mg, 0.267 mmol) in THF (5 mL) at 0° C. was added 1.0 M solutionof KOtBu in THF (0.8 mL 0.8034 mmol). The reaction was allowed to stirat room temperature for 15 min followed by addition of 3-(methylcarbamoyl) benzene sulfonyl chloride (187 mg, 0.801 mmol). The reactionwas allowed to stir at room temperature for 16 h. After completion(monitored by TLC), the reaction mixture was quenched with water andextracted ethyl acetate. The organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by Combi flash column chromatography using a gradient method of40-60% EtOAc/Heptane to afford the title compound 111(110 mg, 88%) as anoff-white solid. TLC: 70% EtOAc (Rf: 0.5). LCMS Calculated forC₂₁H₂₂N₆O₅S: 470.14; Found: 471.8 (M+1).

Synthesis 3-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl) benzo[d]isoxazol-3-yl) sulfonyl)-N-methylbenzamide

To a stirred solution of 3-(N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl) sulfamoyl)-N-methyl benzamide111 (110 mg, 0.233 mmol) in DMF (1.5 mL) at 0° C. was added DIPEA (122mg, 0.699 mmol), T₃P (111 mg, 0.349 mmol). The reaction mixture wasallowed to stir at the room temperature for 10 min. After that, apre-dissolved solution of propiolic acid (44.6 mg, 0.63 mmol) in T₃P(0.304g, 0.95 mmol) was added dropwise. The reaction was stirred at theroom temperature for 4 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure. The crudecompound was purified by prep. HPLC to afford the title compound (5.5mg, 3.3%) as an off-white solid. TLC: 10% MeOH/DCM (Rf: 0.2). LCMSCalculated for C₂₄H₂₂N₆O₆S: 522.13; Found: 523.47 (M−1). (See Table 1for analytical data)

Synthetic Example 53 AND 54

Synthesis of 4-hydroxy-N-((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl)but-2-ynamide

To a stirred solution of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride 25 (0.1 g, 0.208 mmol) in DMF (1 mL) at 0° C. was addedDIPEA (0.11 mL, 0.626 mmol), T₃P 50% solution in EtOAc (0.198 mL, 0.312mmol) followed by 4-hydroxybut-2-ynoic acid (41 mg, 0.416 mmol). Thereaction was allowed to stir at the room temperature for 4 h. Aftercompletion (reaction monitored by TLC), the reaction mixture wasconcentrated. The crude compound was purified by using prep-HPLC toafford the title compound (20 mg, 18.34%) as an off-white solid; TLC:10% MeOH/DCM (Rf: 0.6). (See Table 1 for analytical data).

Synthesis of (E)-4-methoxy-N-((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)but-2-enamide

To a stirred solution of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride 25 (0.1 g, 0.208 mmol) in DMF (1 mL) at 0° C. was addedDIPEA (0.11 mL, 0.626 mmol), T₃P 50% solution in EtOAc (0.198 mL, 0.312mmol) followed by (E)-4-methoxybut-2-enoic acid (48 mg, 0.416 mmol). Thereaction was allowed to stir at the room temperature for 4 h. Aftercompletion (reaction monitored by TLC), the reaction mixture wasconcentrated. The crude compound was purified by using prep-HPLC toafford the title compound (22.5 mg, 18.86%) as an off-white solid; TLC:10% MeOH/DCM (Rf: 0.6). (See Table 1 for analytical data).

Synthetic Example 55

Synthesis of tert-butyl N-[[2-[3-methyl-5-[[[3-(methylcarbamoyl)phenyl]sulfonylamino] carbamoyl] phenyl]-4-pyridyl] methyl] carbamate(112)

To a stirred solution of tert-butyl((2-(3-(hydrazinecarbonyl)-5-methylphenyl) pyridin-4-yl)methyl)carbamate36 (0.25 g, 0.701 mmol) in THF: Pyridine (10 mL, 1:1) at the roomtemperature was added 3-(methylcarbamoyl)benzenesulfonyl chloride (163mg, 0.701 mmol). The reaction was allowed to stir at room temperaturefor 3 h. After completion (monitored by TLC), the reaction mixture wasneutralized with 1N HCl and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byCombi flash column chromatography using a gradient method of 40-48%EtOAc/Heptane to afford the title compound 112 (220 mg, 56.70%) as awhite solid. TLC: 60% EtOAc/Heptane (Rf: 0.4); LCMS Calculated forC27H31N5O6S: 553.20; Found: 554.01 (M+1).

Synthesis of 3-((2-(3-(4-(aminomethyl) pyridin-2-yl)-5-methylbenzoyl)hydrazineyl) sulfonyl)-N-methylbenzamide hydrochloride (113)

To a stirred solution of tert-butyl((2-(3-methyl-5-(2-((3-(methylcarbamoyl) phenyl) sulfonyl)hydrazine-1-carbonyl)phenyl)pyridin-4-yl)methyl)carbamate 112 (170 mg,0.307 mmol) in DCM (3.4 mL) at 0° C. was added 4M HCl in 1,4-Dioxane(1.7 mL). The reaction was allowed to stir at room temperature for 2 h.After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. Crude compound was washed withdiethyl ether and heptane to afford the title compound 113 (0.130 g, HClsalt) as a brown solid. TLC: 10% MeOH/DCM (Rf: 0.5). LCMS Calculated forC20H22ClN5O5S: 489.12; Found: 454.08 (Freebase+1).

Synthesis of N-methyl-3-[[[3-methyl-5-[4-[(prop-2-ynoylamino)methyl]-2-pyridyl]benzoyl] amino] sulfamoyl] benzamide

To a stirred solution of 3-((2-(3-(4-(aminomethyl)pyridin-2-yl)-5-methylbenzoyl) hydrazineyl) sulfonyl)-N-methylbenzamidehydrochloride 113 (80 mg, 0.163 mmol) in DMF (1 mL) at 0° C. was addedEt₃N (0.068 mL, 0.489 mmol). The reaction mixture was stirred 15 minfollowed by addition of propiolic acid (13 mg, 0.195 mmol) and T₃P 50%solution in EtOAc (0.311 mL, 0.489 mmol). The reaction mixture wasallowed to stir at the room temperature for 3 h. After completion(reaction monitored by TLC), the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The crude compound was purified by using preparative HPLC toafford the title compound (23 mg, 28.04%) as an off-white solid. TLC:10% MeOH/DCM (Rf: 0.5). (See Table 1 for analytical data)

Synthetic Example 56

Synthesis of 4-bromo-2-fluoro-6-methoxybenzonitrile (115)

To a stirred solution of 4-bromo-2,6-difluorobenzonitrile 114 (50 mg,229.35 mmol) in MeOH (500 mL) was added NaOMe (14.86 g, 275.22 mmol) andthe reaction mixture was allowed to stir at 0° C. for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice water and extracted with ethyl acetate. The organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure at 30° C.to afford the title compound 115 (55 g, crude) as a yellow solid. TLC:100 EtOAc (Rf: 0.6). LCMS Calculated for C8H5BrFNO: 228.95; Found:229.5(M+1). The crude compound was used in the next step withoutpurification.

Synthesis of 6-bromo-4-methoxybenzo[d]isoxazol-3-amine (116)

To a stirred solution of 4-bromo-2-fluoro-6-methoxybenzonitrile 115 (15g, 65.20 mmol) in 6:1 mixture of DMF: H₂O (7 mL) at room temperature wasadded N-hydroxy acetamide (14.68 g, 195.61 mmol) and followed by K₂CO₃(27 g, 195.6 mmol). The reaction mixture was allowed to stir at 70° C.for 16 h. After completion (monitored by TLC), the reaction mixture waspoured in ice water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by Combi flashchromatography using a gradient method of 70% EtOAc/Heptane to affordthe title compound 116 (7g, 44.19%) as a white solid. TLC: 100% EtOAc(Rf: 0.50); LCMS Calculated for C8H7BrN₂O₂: 241.97; Found: 242.02 (M+1).

Synthesis ofN-(6-bromo-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide(117)

To a stirred solution of 6-bromo-4-methoxybenzo[d]isoxazol-3-amine 116(1 g, 4.11 mmol) in THF (10 mL) was added NaOtPn (1.18 g, 12.34 mmol)followed by 2,6-dimethoxybenzenesulfonyl chloride (3.40 g, 14.4 mmol)and the reaction mixture was allowed to stir at the room temperature for2 h. After completion (monitored by TLC), the reaction mixture wasquenched with ice water and extracted with ethyl acetate. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by combi flash chromatography(neutral alumina) to afford the title compound 117 (1 g, 54.94%) as ayellow solid. TLC: 100 EtOAc (Rf: 0.6). LCMS Calculated forC16H15BrN2O6S:441.98; Found:442.5 (M+1).

Synthesis of tert-butyl 4-(3-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) phenyl)piperazine-1-carboxylate (118)

To a stirred solution ofN-(6-bromo-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide117 (200 mg, 0.451 mmol) and tert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(210 mg, 0.541 mmol) in a 2:1 mixture of 1,4-Dioxane:H₂O (9 mL) wasadded K₂CO₃ (0.187 g, 1.353 mmol). The reaction mixture was degassedwith Argon followed by addition of Pd(dppf)Cl₂ (33 mg, 0.0451 mmol) anddegassed again for 5 min. The reaction mixture was stirred at 80° C. for12 h. After completion (monitored by TLC), the reaction mixture wasdiluted with ethyl-acetate filtered on a Celite pad and concentratedunder reduced pressure. The crude compound was purified by combiflash-chromatography using a gradient method of 0-30% EtOAc/Heptane toafford the title compound 118 (180 mg, 64.05%) as a pale-yellow solid.TLC: 40% EtOAc/Heptane (Rf: 0.4). LCMS Calculated for C31H36N4O8S:624.23; Found: 625.02 (M+1).

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(3-(4-(2,2,2-trifluoroacetyl)-414-piperazin-1-yl)phenyl) benzo[d]isoxazol-3-yl) benzenesulfonamide (119)

To a stirred solution of tert-butyl 4-(3-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) phenyl)piperazine-1-carboxylate 118 (150 mg, 0.240 mmol) in DCM (2 mL) at 0° C.was added TFA (0.185 mL, 2.401 mmol). The reaction was allowed to stirat room temperature for 2 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure and codistilled with Toluene to afford the title compound 119 (120 mg, crudeTFA salt,) as a brown oil. TLC: 5% MeOH/DCM (Rf: 0.3). LCMS Calculatedfor C28H28F3N4O7S: 621.16: Found: 525.50 (Freebase+1).

Synthesis ofN-(6-(3-(4-acryloylpiperazin-1-yl)phenyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide

To a stirred solution of2,6-dimethoxy-N-(4-methoxy-6-(3-(4-(2,2,2-trifluoroacetyl)-414-piperazin-1-yl)phenyl) benzo[d]isoxazol-3-yl) benzenesulfonamide 119 (120 mg, 0.193mmol) in DMF (2 mL) at 0° C. was added DIPEA (0.101 mL, 0.579 mmol),acryloyl chloride (20 mg, 0.231 mmol) followed by T₃P 50% solution inEtOAc (0.184 mL, 0.289 mmol). The reaction mixture was allowed to stirat room temperature for 12 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure and the crudewas purified by using prep HPLC to afford the title compound (8.9 mg,8%) as an off-white solid. TLC: 5% MeOH/DCM (Rf: 0.5). (See analyticaldata in Table 1).

Synthetic Example 57

Synthesis of N-[[1-[[4-methoxy-3-[(2-methoxyphenyl)sulfonylamino]-1,2-benzoxazol-6-yl] methyl] pyrazol-4-yl] methyl]but-2-ynamide

To a stirred solution of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride 25 (0.1 g, 0.208 mmol) in DMF (1 mL) at 0° C. was addedDIPEA (0.11 mL, 0.626 mmol), T₃P 50% solution in EtOAc (0.198 mL, 0.312mmol) followed by but-2-ynoic acid (35 mg, 0.416 mmol). The reaction wasallowed to stir at the room temperature for 4 h. After completion(monitored by TLC), the reaction mixture was evaporated under reducedpressure. The crude compound was purified by using prep HPLC to affordthe title compound (20 mg, 18.86%) as an off-white solid; TLC: 10%MeOH/DCM (Rf: 0.6). (See Table 1 for analytical data).

Synthetic Example 58

Synthesis of tert-butyl 4-(2-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) phenyl)piperazine-1-carboxylate (120)

To a stirred solution ofN-(6-bromo-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide117 (200 mg, 0.451 mmol) and tert-butyl4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(210 mg, 0.541 mmol) in a 2:1 mixture of 1,4-Dioxane:H₂O (9 mL) wasadded K₂CO₃ (0.187 g, 1.353 mmol). The reaction mixture was degassedwith Argon followed by addition of Pd(dppf)Cl₂ (33 mg, 0.0451 mmol) anddegassed again for 5 min. The reaction mixture was stirred at 80° C. for12 h. After completion (monitored by TLC), the reaction mixture wasdiluted with ethyl-acetate filtered on Celite pad and the filtrate wasconcentrated under reduced pressure. The crude compound was purified bycombi flash-chromatography using a gradient method of 10-50%EtOAc/Heptane to afford the title compound 120 (220 mg, 72.36%) as apale-yellow solid.

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(2-(4-(2,2,2-trifluoroacetyl)-414-piperazin-1-yl)phenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(121)

To a stirred solution of tert-butyl 4-(2-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) phenyl)piperazine-1-carboxylate 120 (150 mg, 0.240 mmol) in DCM (2 mL) at 0° C.was added TFA (0.185 mL, 2.401 mmol). The reaction was allowed to stirat room temperature for 2 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure and codistilled with Toluene to afford the title compound 121 (200 mg, crudeTFA salt) as a brown gummy solid. TLC: 5% MeOH/DCM (Rf: 0.3). LCMSCalculated for C28H28F3N4O7S: 621.16: Found: 525.50 (Freebase+1).

Synthesis ofN-(6-(2-(4-acryloylpiperazin-1-yl)phenyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide

To a stirred solution of2,6-dimethoxy-N-(4-methoxy-6-(2-(4-(2,2,2-trifluoroacetyl)-414-piperazin-1-yl)phenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide121 (100 mg, 0.160 mmol) in DMF (2 mL) at 0° C. was added DIPEA (0.083mL, 0.48 mmol), acryloyl chloride (14 mg, 0.193 mmol) followed by T₃P50% solution in EtOAc (0.152 mL, 0.24 mmol) and reaction mixture wasallowed to stir at room temperature for 12 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure and the crude was purified by using prep HPLC to afford thetitle compound (3.6 mg, 3.87%) as an off-white solid. TLC: 5% MeOH/DCM(Rf: 0.5). (See analytical data in Table 1).

Synthetic Example 59

To a stirred solution of N-(6-(((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamidehydrochloride 91 (0.1 g, 0.202 mmol) in DMF (1 mL) at 0° C. was addedTEA (0.0425 mL, 0.303 mmol) followed by ethenesulfonyl chloride (51 mg,0.404 mmol). The reaction was allowed to stir at room temperature for 4h. After completion (monitored by TLC), the reaction mixture wasquenched with ice water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The crude compound was purified byprep HPLC to afford the title compound (1.85 mg, 1.68%) as an off-whitesolid. TLC: 10% MeOH/DCM (Rf: 0.40). (See Table 1 for analytical data).

Synthetic Example 60 AND 61

Synthesis of tert-butyl (2-(((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl)amino)-2-oxoethyl) carbamate (122)

To a stirred solution of compound 25 (0.12 g, 0.25 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.13 mL, 0.75 mmol) and (tert-butoxycarbonyl)glycine (29 mg, 0.16 mmol) followed by T₃P 50% solution in EtOAc (0.1mL, 0.16 mmol). The reaction mixture was stirred at the room temperaturefor 16 h. After completion (monitored by TLC), the reaction mixture wasquenched with aqueous ammonium chloride and extracted with ethylacetate. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated to afford the title compound 122 (0.110 g, 74.07%) as awhite solid. TLC: 10% MeOH/DCM (Rf: 0.5). LCMS Calculated forC27H32N6O8S: 600.20; Found: 601.5 (M+1).

Synthesis of 2-amino-N-[[1-[[4-methoxy-3-[(2-methoxyphenyl)sulfonylamino]-1,2-benzoxazol-6-yl]methyl]pyrazol-4-yl]methyl]acetamide; hydrochloride (123)

To a stirred solution of compound 122 (0.110 g, 0.183 mmol) in DCM (3mL) at 0° C. was added 4M HCl in 1,4-dioxane (3 mL). The reaction wasallowed to stir at room temperature for 2 h. After completion (monitoredby TLC), the reaction mixture was concentrated under reduced pressure.The crude was triturated with diethyl ether and dried under reducedpressure to afford the title compound 123 (150 mg, HCl Salt) as a yellowsolid. TLC: 15% MeOH/DCM (Rf: 0.3); LCMS Calculated forC22H25ClN6O6S:536.12; Found:501.8 (Freebase M+1).

Synthesis ofN-(2-(((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)propiolamide

To a stirred solution of 2-amino-N-((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl)acetamide hydrochloride 123 (60 mg, 0.11 mmol) in DMF (1 mL) at 0° C.was added DIPEA (0.058 mL, 0.33 mmol) followed by T₃P 50% solution inEtOAc (0.1 mL, 0.165 mmol), propiolic acid (15 mg, 0.22 mmol). Thereaction mixture was stirred at the room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure. The crude was purified by using prep-HPLC toafford the title compound (4 mg, 6.55%) as a white solid. TLC: 10%MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthesis ofN-[2-[[1-[[4-methoxy-3-[(2-methoxyphenyl)sulfonylamino]-1,2-benzoxazol-6-yl]methyl]pyrazol-4-yl]methylamino]-2-oxo-ethyl]prop-2-enamide

To a stirred solution of 2-amino-N-((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl)acetamide hydrochloride 123 (60 mg, 0.11 mmol) in DMF (1 mL) at 0° C.was added DIPEA (0.058 mL, 0.33 mmol) and followed by T₃P 50% solutionin EtOAc (0.1 mL, 0.165 mmol) and acrylic acid (15 mg, 0.22 mmol). Thereaction mixture was stirred at the room temperature for 2 h. Aftercompletion monitored by TLC), the reaction mixture was concentratedunder reduced pressure which was purified by using prep-HPLC to affordthe title compound (13.2 mg, 21.63%) as a white solid. TLC: 10% MeOH/DCM(Rf: 0.5). (See Table 1 for analytical data).

Synthetic Example 62

Synthesis of ethyl1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazole-4-carboxylate (124)

To a stirred solution of 4-(bromomethyl)-2-fluoro-6-methoxybenzonitrile87 (1 g, 4.01 mmol) in acetonitrile (5 mL) at the room temperature wasadded Cs₂CO₃ (5.2 g, 16.04 mmol) followed by ethyl1H-pyrazole-4-carboxylate (0.674 g, 4.81 mmol) and the reaction mixturewas heated at 70° C. for 6 h. After completion (monitored by TLC), thereaction mixture was quenched with ice water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by Combi-flash chromatography using a gradient method of 40-70%EtOAc/Heptane to afford the title compound 124 (800 mg, 45.4%) as abrown semi solid. TLC: 80% EtOAc/Heptane (Rf: 0.45). LCMS Calculated forC15H14FN3O3: 303.10; Found: 304.08 (M+1).

Synthesis of ethyl1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazole-4-carboxylate(125)

To a stirred solution of ethyl1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazole-4-carboxylate 124 (800mg, 2.63 mmol) in a 5:1 mixture of DMF:H₂O (6 mL) at room temperaturewas added acetohydroxamic acid (59 mg, 7.91 mmol) followed by K₂CO₃(2.18 g, 15.78 mmol). The reaction mixture was allowed to stir at 60° C.for 16 h. After completion (monitored by TLC), the reaction mixture wasquenched with ice water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byCombi flash chromatography using a gradient method of 30-50%EtOAc/Heptane to afford the title compound 125 (800 g, 95.9%) as a brownsemi solid. TLC: 80% EtOAc/Heptane (Rf: 0.40). LCMS Calculated forC15H16N4O4: 316.12; Found: 317.02 (M+1).

Synthesis of ethyl1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazole-4-carboxylate(126)

To a stirred solution of ethyl1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazole-4-carboxylate 125 (0.800 g, 2.52 mmol) in THF (5 mL)at 0° C. was added 1M tBuOK in THF (7.5 mL, 7.58 mmol) followed by2-methoxybenzenesulfonyl chloride (0.52 g, 3.02 mmol) and the reactionwas allowed to stir at the room temperature for 3 h. After completion(monitored by TLC), the reaction mixture was quenched with water andextracted with Ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude compound was purified by Combi flash chromatography using agradient method of 40-60% EtOAc/Heptane to afford the title compound 126(300 mg, 24.39%) as a brown solid. TLC: 80% EtOAc/Heptane (Rf: 0.35).LCMS Calculated for C22H22N4O7S: 486.12; Found: 487.03 (M+1).

Synthesis of1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazole-4-carboxylicacid (127)

To a stirred solution of compound ethyl1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazole-4-carboxylate 126(150 mg, 0.308 mmol) a mixture of (5:1) in THF-H₂O (6 mL) at 0° C.,LiOH·H₂O (64 mg, 1.54 mmol) was added, and the reaction was allowed tostir at the room temperature for 12 h. After completion (monitored byTLC), the reaction mixture neutralized with 1N HCl ˜pH 7.0 and extractedwith Ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude compound was purifiedby Combi flash column chromatography using a gradient method of 3-5%MeOH/DCM to afford the title compound 127 (6 mg, 11.36%) as an off-whitesolid. TLC: 5% MeOH/DCM (Rf: 0.5). LCMS Calculated for C20H18N4O7S:458.09; Found: 459.5 (M+1).

Synthesis of N-(cyanomethyl)-1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazole-4-carboxamide

To a stirred solution of 1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido)benzo[d]isoxazol-6-yl) methyl)-1H-pyrazole-4-carboxylic acid 127 (60 mg,0.130 mmol) in DMF (2 mL) at 0° C. was added DIPEA (0.068 mL, 0.39mmol), pre-dissolved solution of 2-aminoacetonitrile (17 mg, 0.156 mmol)in DMF (0.5 mL), followed by HATU (74 mg, 0.195 mmol). The reaction wasallowed to stir at the room temperature for 16 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure. The crude compound was purified by using prep. HPLC to affordthe title compound (15 mg, 23.43%) as an off-white solid. TLC: 10%MeOH/DCM (Rf: 0.5) (See analytical data for Table 1)

Synthetic Example 63

Synthesis of ethyl1-(4-cyano-3-fluoro-5-methoxybenzyl)piperidine-4-carboxylate (128)

To a stirred solution of 4-(bromomethyl)-2-fluoro-6-methoxybenzonitrile87 (0.2 g, 0.819 mmol) in acetonitrile (5 mL) at the room temperaturewas added Cs₂CO₃ (0.8 g, 2.45 mmol) followed by ethyl 1-(methylsulfonyl)piperidine-4-carboxylate (0.231 g, 0.982 mmol) and reaction mixture washeated at 70° C. for 6 h. After completion (monitored by TLC), reactionmixture was quenched with ice water and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byCombi-flash chromatography using a gradient method of 40-70%EtOAc/Heptane to afford the title compound 128 (0.180 g, 68.70%) as abrown semi solid. TLC: 80% EtOAc/Heptane (Rf: 0.45). LCMS Calculated forC17H21FN2O3: 320.15; Found: 321.02 (M+1).

Synthesis ethyl1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)piperidine-4-carboxylate(129)

To a stirred solution of compound ethyl1-(4-cyano-3-fluoro-5-methoxybenzyl)piperidine-4-carboxylate 128 (0.18g, 0.56 mmol) in a 6:1 mixture of DMF: H₂O (7 mL) at the roomtemperature was added acetohydroxamic acid (0.126 g, 1.68 mmol) followedby K₂CO₃ (0.465 g, 3.37 mmol). The reaction mixture was allowed to stirat 60° C. for 16 h. After completion (monitored by TLC), the reactionmixture was quenched with ice water and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byCombi flash chromatography using a gradient method of 30-60%EtOAc/Heptane to afford the title compound 129 (0.150 g, 80.21%) as anoff-white solid. TLC: 80% EtOAc/Heptane (Rf: 0.40). LCMS Calculated forC17H23N3O4: 333.17; Found: 334.05 (M+1).

Synthesis ethyl1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)piperidine-4-carboxylate(130)

To a stirred solution of ethyl1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)piperidine-4-carboxylate129 (0.150 g, 0.449 mmol) in THF (3 mL) at 0° C. was added tBuOK 1 M inTHF (0.9 mL, 0.899 mmol) followed by 2-methoxybenzenesulfonyl chloride(185 mg, 0.898 mmol) and the reaction was allowed to stir at 0° C. for 3h. After completion (monitored by TLC), the reaction mixture was dilutedwith DCM, water was added and extracted. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by Combi flash columnchromatography using a gradient method of 40-60% EtOAc/Heptane to affordthe title compound 130 (120 mg, 54.09%) as an off-white solid. TLC: 80%EtOAc/Heptane (Rf: 0.35). LCMS Calculated for C24H29N3O7S: 503.17;Found: 504.03 (M+1).

Synthesis1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)piperidine-4-carboxylicacid (131)

To a stirred solution of ethyl1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)piperidine-4-carboxylate130 (120 mg, 0.238 mmol) in a mixture of (5:1) in THF-H₂O (6 mL) at 0°C., LiOH·H₂O (30 mg, 0.714 mmol) was added. The reaction was allowed tostir at the room temperature for 12 h. After completion (monitored byTLC), the reaction mixture was neutralized with 1N HCl ˜pH 7.0 andextracted with Ethyl acetate. The organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by Combi flash column chromatography using a gradient method of3-5% MeOH/DCM to afford the title compound 131 (100 mg, 88.49%) as anoff-white solid. TLC: 5% MeOH/DCM (Rf: 0.5). LCMS Calculated forC22H25N3O7S: 475.14; Found: 476.05 (M+1).

Synthesis ofN-(cyanomethyl)-1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)piperidine-4-carboxamide

To a stirred solution of1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)piperidine-4-carboxylicacid 131 (100 mg, 0.210 mmol) in DMF (2 mL) at 0° C. was added DIPEA(0.11 mL, 0.630 mmol), pre-dissolved solution of 2-aminoacetonitrile (14mg, 0.252 mmol) in DMF (0.5 mL), followed by HATU (119 mg, 0.315 mmol).The reaction was allowed to stir at the room temperature for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure. The crude compound was purified using prep HPLCto afford the title compound (8.5 mg, 23.43%) as an off-white solid.TLC: 10% MeOH/DCM (Rf: 0.5) (See Table 1 for analytical data).

Synthetic Example 64

To a stirred solution of compoundN-[6-[(4-amino-1-piperidyl)methyl]-4-methoxy-1,2-benzoxazol-3-yl]-2-methoxy-benzenesulfonamide110 (50 mg, 0.103 mmol) in DMF (1 mL) at 0° C. was added DIPEA (0.054mL, 0.310 mmol) and pre-dissolved solution of propiolic acid (14 mg,0.206 mmol) in DMF (0.5 mL), followed by HATU (78 mg, 0.206 mmol). Thereaction was allowed to stir at the room temperature for 16 h. Aftercompletion (reaction monitored by TLC), reaction mixture wasconcentrated under reduced pressure. The crude compound was purified byusing prep HPLC to afford the title compound (15 mg, 29.41%) as anoff-white solid. TLC: 10% MeOH/DCM (Rf: 0.5) LCMS Calculated forC24H26N4O6S: 498.16; Found: 499.2 (M+1). (See Table 1 for analyticaldata)

Synthetic Example 65

Synthesis of methyl4-(N-(6-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-3-methoxybenzoate(132)

To a stirred solution of tert-butyl((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl) carbamate 22 (200 mg, 0.5356 mmol) in THF (3 mL) at 0° C. wasadded NaOtBu (154 mg, 1.6068 mmol) followed by methyl 4-(Chlorosulfonyl)-3-methoxybenzoate (283 mg, 1.0712 mmol). The reaction wasallowed to stir at room temperature for 2 h. After completion (monitoredby TLC), the reaction mixture was quenched with ice-water and extractedwith ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude was purified by Combiflash chromatography to afford the title compound 132 (180 g, 55.90%) asan off-white solid. TLC: 100% EtOAc (Rf: 0.5) LCMS Calculated forC27H31N5O9S: 601.18; Found: 602.5 (M+1).

Synthesis of methyl3-methoxy-4-(N-(4-methoxy-6-((4-(((2,2,2-trifluoroacetyl)-14-azaneyl)methyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)sulfamoyl)benzoate(133)

To a stirred solution of compound methyl4-(N-(6-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-3-methoxybenzoate132 (90 mg, 0.1495 mmol) in DCM (1 mL) at 0° C. was added TFA (0.12 mL,1.49 mmol). The reaction was stirred at room temperature for 1 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure to afford title compound 133 (92 mg, 100%, LCMSCalculated for C24H23F₃N5O₈S: 598.12; Found: 502.5 (M+1).

Synthesis ofmethyl-3-methoxy-4-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl) benzo[d]isoxazol-3-yl) sulfamoyl)benzoate (134)

To a stirred solution of methyl3-methoxy-4-(N-(4-methoxy-6-((4-(((2,2,2-trifluoroacetyl)-14-azaneyl)methyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)sulfamoyl)benzoate133 (80 mg, 0.133 mmol) in DMF (1 mL) at 0° C. was added propiolic acid(11 mg, 0.160 mmol), DIPEA (0.09 mL, 0.532 mmol) followed by T₃P 50%solution in EtOAc (0.126 g, 0.199 mmol). The reaction was allowed tostir at the room temperature for 4 h. After completion (monitored byTLC), the reaction mixture was quenched with ice-water and extractedwith ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the title compound 134(45 mg, crude) as a white solid. TLC: 80% EtOAc/Heptane (Rf: 0.4 LCMSCalculated for C25H23N5O8S: 553.13; Found: 554.8 (M+1). Crude materialused in the next step further any purification

Synthesis of3-methoxy-4-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)sulfamoyl)benzoicacid

To a stirred solution ofmethyl-3-methoxy-4-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl) benzo[d]isoxazol-3-yl) sulfamoyl) benzoate 134 (45 mg, 0.0182mmol) in a 1:1 mixture of THF-H₂O (2 mL) was added LiOH·H₂O (8.5 mg,0.203 mmol). The reaction mixture was stirred at the room temperaturefor 1 h. The progress of the reaction was monitored by TLC. The reactionmixture was neutralized with 2 N HCl and extracted with ethyl acetate.The organic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude was purified by prep-HPLC purification toafford the title compound (6.2 mg, 14.41%) as an off-white solid. TLC:100% EtOAc/Heptane (Rf: 0.2) (See Table 1 for analytical data).

Synthetic Example 66

Synthesis (2-chloro-6-methoxypyridin-4-yl)methanol (136)

To a stirred solution of compound 135 (5 g, 29.00 mmol) in THF (50 mL)at 0° C. was added NaBH₄ (1.6 g, 44.00 mmol) and the resulting reactionmixture was stirred at 0° C. for 2 h. After completion of the reaction(monitored by TLC), the reaction mixture was neutralized with 1N HCl andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford the title compound 136 (4.5 g, 88.93%) as a yellow solid. TLC:30% EtOAc/Heptane (Rf: 0.35). LCMS Calculated for C7H8ClNO2: 173.02;Found: 172.8 (M+1).

Synthesis of tert-butyl ((1-((2-chloro-6-methoxypyridin-4-yl)methyl)-1H-pyrazol-4-yl) methyl) carbamate (137)

To a stirred solution of compound 136 (4.5 g, 25.91 mmol) in ACN (50 mL)at 0° C. was added Cs₂CO₃ (25.32 g, 77.73 mmol), tert-butyl((1-(methylsulfonyl)-1H-pyrazol-4-yl) methyl) carbamate (8.5 g, 31.09mmol) and the resulting reaction mixture was stirred at 0° C. for 2 h.After completion (monitored by TLC), the reaction mixture was quenchedwith ice water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to afford the title compound 137 (2 g, 21.88%) as ayellow solid. TLC: 40% EtOAc/Heptane (Rf: 0.35). LCMS Calculated forC16H21ClN4O3: 352.13; Found: 353.9 (M+1).

Synthesis of tert-butyl ((1-((2-hydrazineyl-6-methoxypyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (138)

To a stirred solution of compound 137 (0.5 g, 1.41 mmol) in EtOH (5 mL)at 0° C. was added hydrazine hydrate (0.1 mL, 2.12 mmol) and theresulting reaction mixture was stirred at 70° C. for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure and extracted with ethyl acetate. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford the title compound 138 (0.3 g, 60.85%) as a yellowsolid. TLC: 30% EtOAc/Heptane (Rf: 0.35). LCMS Calculated forC16H24N6O3: 348.19; Found: 349.2 (M+1).

Synthesis of tert-butyl ((1-((3-amino-5-methoxy-[1,2,4] triazolo[4,3-a]pyridin-7-yl) methyl)-1H-pyrazol-4-yl) methyl) carbamate (139)

To a stirred solution of compound 138 (500 mg, 1.435 mmol) in mixture of(4:1) EtOH: H₂O (5 mL) at room temperature was added Cyanogen Bromide(182 mg, 1.72 mmol) and the resulting reaction mixture was stirred atroom temperature for 16 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure and extractedwith ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the title compound 139(260 mg, 48.59%) as an off-white solid. TLC: 40% EtOAc/Heptane (Rf:0.3). LCMS Calculated for C17H23N7O3: 373.19; Found: 374.1 (M+1).

Synthesis of tert-butyl((1-((5-methoxy-3-((2-methoxyphenyl)sulfonamido)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(140)

To a stirred solution of compound 139 (260 mg, 0.696 mmol) in THF (5 mL)was added sodium tert-Pentoxide (383 mg, 3.48 mmol) followed by2-methoxybenzenesulfonyl chloride (287 mg, 1.39 mmol) and the reactionmixture was allowed to stir at 60° C. for 16 h. After completion(reaction monitored by TLC), the reaction mixture was quenched with icewater and extracted with ethyl acetate. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by combi flash chromatography (neutral alumina) toafford the title compound 140 (160 mg, 42.32%) as a yellow solid. TLC:80% EtOAc/Heptane (Rf: 0.6). LCMS Calculated for C24H29N7O6S:543.19;Found:544.5 (M+1).

Synthesis of2-methoxy-N-(5-methoxy-7-((4-(((2,2,2-trifluoroacetyl)-14-azaneyl)methyl)-1H-pyrazol-1-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzenesulfonamide(141)

To a stirred solution of compound 140 (70 mg, 0.129 mmol) in DCM (3 mL)at room temperature, TFA (0.2 mL, 1.29 mmol) was added and the reactionmixture was allowed to stir at room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure to afford the title compound 141 (70 mg, TFAsalt) as a brown liquid. TLC: 10% MeOH/DCM (Rf: 0.5). LCMS Calculatedfor C21H20F₃N7O5S: 539.12; Found: NA.

Synthesis ofN-((1-((5-methoxy-3-((2-methoxyphenyl)sulfonamido)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide

To a stirred solution of compound 141 (70 mg, 0.129 mmol) in DMF (3 mL)at room temperature was added DIPEA (0.067 mL, 0.389 mmol), T₃P 50%solution in EtOAc (0.123 mL, 0.193 mmol) followed by propiolic acid (10mg, 0.154 mmol) and the reaction was allowed to stir at the roomtemperature for 4 h. After completion (monitored by TLC), the reactionmixture was quenched with ice-water and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous Na₂SO₄,and concentrated to afford the title compound (14 mg, 21.87%) as a whitesolid. TLC: 10% MeOH/DCM (Rf: 0.5). (See Table 1 for analytical data).

Synthetic Example 67

Synthesis of ethyl1-(4-cyano-3-fluoro-5-methoxybenzyl)pyrrolidine-3-carboxylate (142)

To a stirred solution of 4-(bromomethyl)-2-fluoro-6-methoxybenzonitrile87 (1.5 g, 6.14 mmol) in DMF (10 mL) at the room temperature was addedDIPEA (2.14 mL, 12.29 mmol), followed by ethyl 1-(12-chloraneyl)pyrrolidine-3-carboxylate (1.2g, 6.75 mmol) and the resulting reactionmixture was heated at 60° C. for 16 h. After completion (monitored byTLC), the reaction mixture was quenched with ice cold water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford the title compound 142 (1.3g, 69.14%) as a yellow solid. TLC:100% EtOAc (Rf: 0.5). LCMS Calculated for C16H19FN2O3: 306.14; Found:307.4 (M+1).

Synthesis of ethyl 1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)pyrrolidine-3-carboxylate (143)

To a stirred solution of ethyl1-(4-cyano-3-fluoro-5-methoxybenzyl)pyrrolidine-3-carboxylate 142 (1.3g, 4.24 mmol) in 6:1 mixture of DMF: H₂O (7 mL) at room temperature wasadded N-hydroxy acetamide (0.955 g, 12.73 mmol) and followed by K₂CO₃(3.5 g, 25.44 mmol). The reaction mixture was allowed to stir at 70° C.for 16 h. After completion (monitored by TLC), the reaction mixture waspoured in ice water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by Combi flashchromatography using a gradient method of 70% EtOAc/Heptane to affordthe title compound 143 (600 mg, 46.15%) as a brown solid. TLC: 100%EtOAc (Rf: 0.50); LCMS Calculated for C16H21N3O4: 319.15; Found: 320.02(M+1).

Synthesis of ethyl1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)pyrrolidine-3-carboxylate(144)

To a stirred solution of ethyl1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)pyrrolidine-3-carboxylate143 (600 mg, 1.87 mmol) in mixture of THF:pyridine (20 mL, 3:1) at roomtemperature was added 2-methoxybenzenesulfonyl chloride (465 mg, 2.25mmol). The reaction was allowed to stir at 60° C. for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was neutralized with1N HCl and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The crude compound was purified by Combi flash columnchromatography using a gradient method of 40-48% EtOAc/Heptane to affordthe title compound 144 (300 mg, 61.11%) as a white solid. TLC: 80%EtOAc/Heptane (Rf: 0.4); LCMS Calculated for C23H27N3O7S: 489.16; Found:490.01 (M+1). [0763]1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)pyrrolidine-3-carboxylicacid (145)

To a stirred solution of ethyl1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)pyrrolidine-3-carboxylate 144 (0.3g, 0.612 mmol) ina 1:1 mixture of THF-H₂O (5 mL) was added LiOH·H₂O (77 mg, 1.83 mmol).The reaction mixture was stirred at the room temperature for 16 h. Theprogress of the reaction was monitored by TLC. After completion, thereaction mixture was quenched with citric acid and concentrated underreduced pressure. The crude was purified by combi-flash chromatography10-15% of MeOH/DCM to afford the title compound 145 (0.250 g, 88.65%) asan off-white solid. TLC: 5% MeOH/DCM (Rf: 0.2) LCMS Calculated forC21H23N3O7S: 461.13; Found: 462.4 (M+1).

Synthesis of N-(cyanomethyl)-1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl) pyrrolidine-3-carboxamide

To a stirred solution of1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)pyrrolidine-3-carboxylicacid 145 (50 mg, 0.108 mmol) in DMF (2 mL) at 0° C. was added2-aminoacetonitrile (7 mg, 0.130 mmol), DIPEA (0.055 mL, 0.324 mmol)followed by HATU (123 mg, 0.324 mmol). The reaction was allowed to stirat the room temperature for 16 h. After completion of the reaction(monitored by TLC), the mixture was concentrated under reduced pressure.The crude was purified by using combi-flash chromatography 10-15%EtOAc/Heptane to afford the title compound (3 mg, 5.55%) as an off-whitegummy solid. TLC: 10% MeOH/DCM (Rf: 0.6). (See Table 1 for analyticaldata).

Synthetic Example 68

Synthesis of methyl 2-(N-(6-((4-(((tert-butoxycarbonyl) amino)methyl)-1H-pyrazol-1-yl) methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl) benzoate (146)

To a stirred solution of tert-butyl((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate22 (0.5 g, 1.33 mmol) in THF (3 mL) at 0° C. was added 1.0 M solution ofKOtBu (2.67 mL, 2.67 mmol) in THF followed by methyl2-(chlorosulfonyl)benzoate (0.624 mg, 2.66 mmol). The reaction wasallowed to stir at room temperature for 2 h. After completion (monitoredby TLC), the reaction mixture was quenched with water and extracted withethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude was purified by Combiflash (100-200 mesh) column chromatography using a gradient method of20-80% EtOAc/Heptane to afford the title compound 146 (0.3g, 27.42%) asan off-white solid. TLC: 80% EtOAc/Heptane (Rf: 0.5). LCMS Calculatedfor C26H29N5O8S: 571.17; Found: 572.8 (M+1).

Synthesis2-(N-(6-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)benzoicacid (147)

To a stirred solution of methyl 2-(N-(6-((4-(((tert-butoxycarbonyl)amino) methyl)-1H-pyrazol-1-yl) methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl) benzoate 146 (0.3g, 0.52 mmol) in a 1:1 mixture of THF-H₂O (2mL) was added LiOH·H₂O (66 mg, 1.57 mmol). The reaction mixture wasstirred at the room temperature for 16 h. The progress of the reactionwas monitored by TLC. After completion (monitored by TLC), the reactionmixture was quenched with citric acid concentrated under reducedpressure. The crude was purified by combi-flash chromatography 10-15% ofMeOH/DCM to afford the title compound 147 (0.250 g, 85.61%) as a brownsemi solid. TLC: 5% MeOH/DCM (Rf: 0.2) LCMS Calculated for C25H27N5O8S:557.16; Found: 558.4 (M+1).

Synthesis of tert-butyl ((1-((4-methoxy-3-((2-(methylcarbamoyl) phenyl)sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl)carbamate (148)

To a stirred solution of 2-(N-(6-((4-(((tert-butoxycarbonyl) amino)methyl)-1H-pyrazol-1-yl) methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl) benzoic acid 147 (0.15g, 0.269 mmol) in DMF (5 mL) at 0° C.was added Methyl amine hydrochloride (27 mg, 0.40 mmol), DIPEA (0.14 mL,0.807 mmol) followed by HATU (153 mg, 0.403 mmol). The reaction wasallowed to stir at the room temperature for 16 h. After completion(monitored by TLC), the mixture was concentrated under reduced pressure.The crude was purified by using combi-flash chromatography 10-15%EtOAc/Heptane to afford the title compound 148 (0.12g, 78.43%) as awhite solid. TLC: 10% MeOH/DCM (Rf: 0.6). LCMS Calculated forC26H30N6O7S: 570.19; Found: 571.4 (M+1).

Synthesis of2-(N-(4-methoxy-6-((4-(((2,2,2-trifluoroacetyl)-14-azaneyl)methyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)sulfamoyl)-N-methylbenzamide(149)

To a stirred solution of compound 148 (0.2 g, 0.35 mmol) in DCM (2 mL)at 0° C., was added TFA (1 mL) the reaction mixture was allowed to stirat the room temperature for 2 h. After completion (monitored by TLC),the reaction mixture was concentrated under reduced pressure to affordthe title compound 149 (70 mg, TFA salt) as an off-white solid. TLC: 10%MeOH/DCM (Rf: 0.5). LCMS Calculated for C23H22F3N6O6S: 567.13; Found:N.A. This was taken forward for the next step without any furtherpurification.

Synthesis of 2-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl) benzo[d]isoxazol-3-yl) sulfamoyl)-N-methylbenzamide

To a stirred solution of2-(N-(4-methoxy-6-((4-(((2,2,2-trifluoroacetyl)-14-azaneyl)methyl)-1H-pyrazol-1-yl) methyl)benzo[d]isoxazol-3-yl)sulfamoyl)-N-methylbenzamide 149 (60 mg, 0.105mmol) in DMF (5 mL) at 0° C. was added DIPEA (0.055 mL, 0.317 mmol),followed by T₃P (43 mg, 0.136 mmol). The reaction mixture was stirred atthe room temperature for 5 min. After that, a pre-dissolved solution ofpropiolic acid (14 mg, 0.21 mmol) in DMF (0.5 mL) was added dropwise.The reaction was allowed to stir at the room temperature for 4 h. Aftercompletion (monitored by TLC), the reaction mixture concentrated underreduced pressure. The crude was purified by using prep HPLC to affordthe title compound (20 mg, 36.36%) as a white solid. TLC: 10% MeOH/DCM(Rf: 0.5); (See analytical data for Table 1).

Synthetic Example 69

Synthesis of tert-butyl ((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl) carbamate (150)

To a stirred solution of compound 22 (0.150 g, 0.401 mmol) in THF (3 mL)at 0° C. was added tBuOK 1 M in THF (1.2 mL, 1.20 mmol) followed by5-ethyl-2-methoxybenzenesulfonyl chloride (185 mg, 0.898 mmol). Thereaction was allowed to stir at 0° C. for 3 h. After completion(monitored by TLC), reaction mixture was diluted with DCM, water wasadded and extracted with Ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by Combi flash columnchromatography using a gradient method of 40-60% EtOAc/Heptane to affordthe title compound 150 (130 mg, 56.76%) as an off-white solid. TLC: 80%EtOAc/Heptane (Rf: 0.35). LCMS Calculated for C27H33N5O7S: 571.21;Found: 578.03 (M+1).

Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamidehydrochloride (151)

To a stirred solution of tert-butyl ((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate 150 (130 mg, 0.227 mmol) in DCM(2 mL) at 0° C. was added 4M HCl in 1,4-dioxane (2 mL). The reactionmixture was allowed to stir at room temperature for 2 h. Aftercompletion (monitored by TLC), the organic solvent was evaporated underreduced pressure and the residue obtained was triturated withDCM/Heptane to afford 151 (100 mg, salt) as an off-white solid. TLC: 5%MeOH/DCM (Rf: 0.3). LCMS Calculated for C22H26ClN5O5S: 507.13; Found:NA.

Synthesis of N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl) propiolamide

To a stirred solution of compound 151 (100 mg, 0.196 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.068 mL, 0.393 mmol), propiolic acid (15 mg,0.215 mmol) followed by T₃P 50% solution in EtOAc (0.249 mL, 0.392mmol). The reaction mixture was allowed to stir at room temperature for12 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude compound obtained waspurified by using prep HPLC to afford the title compound (14 mg, 13.46%)as a white solid. TLC: 10% MeOH/DCM (Rf: 0.5). (See Table 1 foranalytical data).

Synthetic Example 70

Synthesis of2,3,4,5,6-pentafluoro-N-((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)benzenesulfonamide

To a stirred solution of 25 (50 mg, 0.104 mmol) in DCE (2 mL) at 0° C.was added DIPEA (0.054 mL, 0.312 mmol) followed by2,3,4,5,6-pentafluorobenzenesulfonyl chloride (41 mg, 0.156 mmol). Thereaction was allowed to stir at 100° C. for 12 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure and crude compound was purified by using prep HPLC to affordthe title compound (11.2 mg, 16%) as an off-white solid. TLC: 80%EtOAc/Heptane (Rf: 0.5). (See Table 1 for analytical data).

Synthetic Example 71

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(3-(4-propioloylpiperazin-1-yl) phenyl)benzo[d]isoxazol-3-yl) benzenesulfonamide

To a stirred solution of2,6-dimethoxy-N-(4-methoxy-6-(3-(4-(2,2,2-trifluoroacetyl)-414-piperazin-1-yl)phenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide119 (120 mg, 0.193 mmol) in DMF (2 mL) at 0° C. was added DIPEA (0.101mL, 0.579 mmol), propiolic acid (16 mg, 0.231 mmol) followed by T₃P 50%solution in EtOAc (0.184 mL, 0.289 mmol). The reaction mixture wasallowed to stir at room temperature for 12 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure and the crude compound was purified by using prep HPLC toafford the title compound (26 mg, 23.42%) as a white solid. TLC: 5%MeOH/DCM (Rf: 0.5). (See Table 1 for analytical data)

Synthetic Example 72 AND 73

Synthesis of 2,6-dimethoxy-N-(4-methoxy-6-(3-(4-(vinylsulfonyl)piperazin-1-yl) phenyl) benzo[d]isoxazol-3-yl) benzenesulfonamide

To a stirred solution of compound 119 (0.12 g, 0.193 mmol) in DMF (1 mL)at 0° C. was added TEA (0.081 mL, 0.579 mmol) followed by ethenesulfonyl chloride (36 mg, 0.289 mmol). The reaction was allowed to stirat room temperature for 2 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure to get browngummy crude. The crude was purified by combi-flash chromatography usinggradient of 5%-10% MeOH in DCM to get the desired compound which wasfurther purified by prep HPLC to afford the title compound (10 mg,8.47%) as an off-white solid. TLC: 10% MeOH/DCM (Rf: 0.40). (See Table 1for analytical data).

Synthesis of N-(6-(3-(4-(2-chloroacetyl) piperazin-1-yl)phenyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide

To a stirred solution of compound 119 (0.12 g, 0.193 mmol) in DMF (1 mL)at 0° C. was added TEA (0.081 mL, 0.579 mmol) followed by 2-chloroacetylchloride (32 mg, 0.289 mmol). The reaction was allowed to stir at roomtemperature for 2 h. After completion (monitored by TLC), the reactionmixture was concentrated under reduced pressure to get brown gummycrude. The crude was purified by combi-flash chromatography usinggradient of 5%-10% MeOH in DCM to get desired compound which was furtherpurified by prep HPLC to afford the title compound (9 mg, 7.75%) as anoff-white solid. TLC: 10% MeOH/DCM (Rf: 0.40). (See Table 1 foranalytical data).

Synthetic Example 74

Synthesis ofN-(6-bromo-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide(152)

To a stirred solution of compound 116 (1 g, 4.11 mmol) in THF (10 mL)was added NaOtBu (1.18 g, 12.33 mmol) followed by2-methoxybenzenesulfonyl chloride (1.02 g, 4.93 mmol) and the reactionmixture was allowed to stir at room temperature for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice water and extracted with ethyl acetate. The organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by combi flash chromatography (neutral alumina) toafford the title compound 152 (300 mg, 17.64%) as a brown solid. TLC:80% EtOAc in Heptane (Rf: 0.5). LCMS Calculated forC15H13BrN2O5S:411.97; Found:412.5 (M+1).

Synthesis of tert-butyl 4-(3-(4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isoxazol-6-yl) phenyl) piperazine-1-carboxylate(153)

To a stirred solution of compound 152 (300 mg, 0.725 mmol) andtert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(310 mg, 0.798 mmol) in a 2:1 mixture of 1,4 Dioxane:water (9 mL) wasadded K₂CO₃ (200 mg, 1.45 mmol). The reaction mixture was degassed withArgon atmosphere followed by addition of Pd(dppf)Cl₂ (58 mg, 0.0725mmol) and further degassed for 5 min. The reaction mixture was stirredat 80° C. for 16 h. After completion (monitored by TLC), the reactionmixture was diluted with ethyl-acetate, filtered on Celite pad andconcentrated under reduced pressure. The crude was purified by combiflash-chromatography using a gradient method of 0-30% EtOAc/Heptane toafford the title compound 153 (380 mg, 86.75%) as a pale brown solid.TLC: 80% EtOAc/Heptane (Rf: 0.4). LCMS Calculated for C30H34N4O7S:594.21; Found: 595.02 (M+1).

Synthesis of2-methoxy-N-(4-methoxy-6-(3-(4-(2,2,2-trifluoroacetyl)-414-piperazin-1-yl)phenyl) benzo[d]isoxazol-3-yl)benzenesulfonamide (154)

To a stirred solution of compound 153 (350 mg, 0.588 mmol) in DCM (2 mL)at 0° C. was added TFA (0.47 mL, 5.88 mmol) and the reaction was allowedto stir at the room temperature for 2 h. After completion (monitored byTLC), the reaction mixture was concentrated under reduced pressure andco distilled with ether to afford the title compound 154 (320 mg, crudeTFA salt) as a brown oil. TLC: 5% MeOH/DCM (Rf: 0.3). This was taken tothe next step without further analysis.

Synthesis of2-methoxy-N-(4-methoxy-6-(3-(4-propioloylpiperazin-1-yl)phenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 154 (150 mg, 0.253 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.177 mL, 1.01 mmol), propiolic acid (21 mg,0.303 mmol) followed by T3P as a 50% solution in EtOAc (0.321 mL, 0.506mmol). The reaction mixture was allowed to stir at room temperature for2 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (10 mg, 7.24%) as an off-whitesolid. TLC: 5% MeOH/DCM (Rf: 0.5). (See Table 1 for analytical data).

Synthetic Example 75

tert-butyl 3-(2-bromophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (156)

To a stirred solution of 155 (500 mg, 1.693 mmol) and1-bromo-2-iodobenzene (575 mg, 2.032 mmol) in a 2:1 mixture of 1,4Dioxane: water (9 mL) was added K₂CO₃ (0.701 g, 5.079 mmol). Thereaction mixture was degassed with Argon atmosphere followed by additionof Pd(dppf)Cl₂ (136 mg, 0.169 mmol) and stirred at 80° C. for 12 h.After completion (monitored by TLC), the reaction mixture was dilutedwith ethyl-acetate, filtered on Celite pad and the reaction mixture wasconcentrated under reduced pressure. The crude was purified by combiflash-chromatography using a gradient method of 0-30% EtOAc/Heptane toafford the title compound 156 (400 mg, 72.85%) as a pale brown solid.TLC: 50% EtOAc/Heptane (Rf: 0.4). LCMS Calculated for C15H18BrNO2:323.05; Found: 324.05 (M+1).

tert-butyl3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate(157)

To a stirred solution of 156 (400 mg, 1.233 mmol) in 3:1 mixture of 1,4Dioxane: water (40 mL), was added K₂CO₃ (511 mg, 3.701 mmol) followed byPd(PPh₃)4 (142 mg, 0.1233 mmol) and Bpin₂ (469 mg, 1.849 mmol). Theresulting reaction mixture was stirred at 90° C. for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was cooled to roomtemperature, diluted, and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycombi flash chromatography (using a gradient method of 0-50%EtOAc/Heptane) to afford the title compound 157 (200 mg, 43.66%) as ayellow solid. TLC: 50% EtOAc/Heptane (Rf: 0.5). LCMS Calculated forC21H30BNO4: 371.23; Found: 372.02 (M+1).

Synthesis of tert-butyl3-(2-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate(158)

To a stirred solution of compound 117 (1 g, 2.25 mmol) in mixture ofdioxane:H₂O (5:1, 10 mL) was added K₂CO₃ (915 mg, 6.767 mmol) followedby tert-butyl3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate157 (1.25 g, 3.382 mmol) and the reaction mixture was degassed withargon gas for 10 min. PdCl₂dppf (167 mg, 0.22 mmol) was added and themixture heated at 80° C. for 16 h. After completion (monitored by TLC),the reaction mixture was cooled to room temperature, filtered through acelite pad, diluted with water, and extracted with ethyl acetate. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by combi flashchromatography (neutral alumina) to afford the title compound 158 (1 g,72.99%) as an off-white solid. TLC: 80% EtOAc/Heptane (Rf: 0.6). LCMSCalculated for C31H33N3O8S: 607.20; Found:608.5 (M+1).

Synthesis of tert-butyl 3-(2-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) phenyl)pyrrolidine-1-carboxylate 159

An autoclave was charged with a solution of compound 158 (700 mg 1.151mmol) in MeOH:EtOAc (15 mL, 2:1) and the mixture was degassed withnitrogen. 10% Pd/C (350 mg) was added under nitrogen atmosphere. Thereaction mixture was allowed to stir under hydrogen atmosphere (100 psi)at room temperature for 16 h. After completion (monitored by TLC), thereaction mixture was filtered through a pad of Celite. The filtrate wasconcentrated under reduced pressure. The crude product was purified byCombi flash chromatography (using a gradient method of 0-5% MeOH/DCM) toafford the title compound 159 (150 mg, 21.36%) as a white solid. TLC:50% EtOAc/Heptane (R_(f). 0.6). LCMS Calculated for C31H35N3O8S: 609.21;Found: 610.08 (M+1).

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(2-(1-(2,2,2-trifluoroacetyl)-114-pyrrolidin-3-yl)phenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(160)

To a stirred solution of compound 159 (150 mg, 0.246 mmol) in DCM (2 mL)at 0° C. was added TFA (0.2 mL, 2.460 mmol). The reaction was allowed tostir at the room temperature for 2 h. After completion (monitored byTLC), the reaction mixture was concentrated under reduced pressure andco distilled with toluene to afford the title compound 160 (120 mg,crude salt) as a brown oil. TLC: 5% MeOH/DCM (R_(f). 0.3). The crudematerial was used in the next step without any characterization orpurification.

Synthesis ofN-(6-(2-(1-acryloylpyrrolidin-3-yl)phenyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide

To a stirred solution of compound 160 (100 mg, 0.165 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.057 mL, 0.330 mmol), acrylic acid (14 mg,0.198 mmol) followed by T₃P as a 50% solution in EtOAc (0.157 mL, 0.247mmol). The reaction mixture was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (4 mg, 4.34%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 76

Synthesis of tert-butyl((1-((3-amino-4-methoxy-1H-indazol-6-yl)methyl)-1H-pyrazol-4-yl) methyl) carbamate (161)

To a stirred solution of compound 21 (750 mg, 2.081 mmol) in 6:1 mixtureof DMF: H₂O (7 mL) at room temperature was added hydrazine hydrate (0.31mL, 6.243 mmol) followed by K₂CO₃ (1.72 g, 12.48 mmol). The reactionmixture was allowed to stir at 80° C. for 16 h. After completion(monitored by TLC), the reaction mixture was poured in ice water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude compound was purified by Combi flash chromatography using agradient method of 70% EtOAc/Heptane to afford the title 161 (700 mg,90.32%) as a brown semi solid. TLC: 60% EtOAc (R_(f). 0.50); LCMSCalculated for C18H24N6O3: 372.19; Found: 373.02 (M+1).

Synthesis of tert-butyl3-amino-6-((4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)methyl)-4-methoxy-1H-indazole-1-carboxylate(162)

To a stirred solution of compound 161 (0.6 g, 1.61 mmol) in MeOH (75 mL)at 0° C. was added TEA (0.45 mL, 3.22 mmol) followed by drop-wiseaddition of (Boc)₂O (0.46 mL, 2.094 mmol) and the reaction was allowedto stir for 2 h at room temperature. After completion (monitored byTLC), the reaction mixture was poured to ice-cold water and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by Combi flash chromatography using a gradientmethod of 50% EtOAc/Heptane to afford the title 162 (220 mg, 28.9%) asan off-white solid. TLC: 50% EtOAc/Heptane (R_(f). 0.55); LCMSCalculated for C23H32N6O5: 472.24; Found:473.05 (M+1).

Synthesis of tert-butyl 6-((4-(((tert-butoxycarbonyl) amino)methyl)-1H-pyrazol-1-yl) methyl)-4-methoxy-3-((2-methoxyphenyl)sulfonamido)-1H-indazole-1-carboxylate (163)

To a stirred solution of 162 (100 mg, 0.211 mmol) in THF (6 mL) at 0° C.was added 60% NaH (25 mg, 0.634 mmol) followed by2-methoxybenzenesulfonyl chloride (0.681 g, 3.31 mmol) at roomtemperature and the reaction was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasquenched with saturated ammonium chloride solution and extracted with10% MeOH/DCM. The combined organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to afford thetitle compound 163 (150 mg, crude) as a gummy brown solid. TLC: 10%MeOH/DCM (R_(f). 0.5); LCMS Calculated for C25H32N4O7S:532.20:Found:533.02 (M+1). The crude compound was used in the next step withoutany purification.

Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxy-1H-indazol-3-yl)-2-methoxybenzenesulfonamidedihydrochloride (164)

To a stirred solution of compound 163 (100 mg, 0.155 mmol) in DCM (3 mL)at 0° C. was added 4M HCl in 1,4-Dioxane (3 mL) and the reaction wasallowed to stir at the room temperature for 2 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure. The crude was washed with diethyl ether and heptane and driedunder reduced pressure to afford the title compound 164 (110 mg, salt)as a pale brown semi-solid. TLC: 10% MeOH/DCM (R_(f). 0.5). It was usedas obtained in the next step.

Synthesis of N-((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)-1H-indazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide

To a stirred solution of compound 164 (100 mg, 0.194 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.1 mL, 0.582 mmol), T₃P (50% solution inEtOAc, 0.185 mL, 0.291 mmol) followed by propiolic acid (9.2 mg, 0.132mmol). The reaction was allowed to stir at the room temperature for 1 h.After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure, quenched with ice water, andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude was purified by prep HPLC to afford the title compound (7.6mg, 6.7%) as an off-white solid. TLC: 5% MeOH/DCM (R_(f). 0.6). (SeeTable 1 for analytical data).

Synthetic Example 77

Synthesis of 2-methoxy-N-(4-methoxy-6-((4-(vinylsulfonamido)piperidin-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 110 (0.1 g, 0.207 mmol) in DMF (1 mL)at 0° C. was added TEA (0.087 mL, 0.621 mmol) followed by Ethenesulfonyl chloride (31 mg, 0.248 mmol). The reaction was allowed to stirat room temperature for 2 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure, to afford abrown gummy crude. The crude was purified by combi-flash chromatographyusing gradient of 5-10% to get desired compound which was furtherpurified by prep HPLC to afford the title compound (20 mg, 18%) as anoff-white solid. TLC: 10% MeOH/DCM (Rf: 0.40). (See Table 1 foranalytical data).

Synthetic Example 78,79 AND 80

Synthesis ofN-(6-((4-(((4-fluorophenyl)sulfonamido)methyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide

To a stirred solution of compound 50 (100 mg, 0.208 mmol) in DCM (3 mL)at 0° C. was added TEA (0.087 mL, 0.625 mmol) followed by4-fluorobenzenesulfonyl chloride (48 mg, 0.249 mmol). The reaction wasallowed to stir at the room temperature for 4 h. After completion(monitored by TL C), the reaction mixture was concentrated under reducedpressure to get a brown gummy crude which was purified by combi-flashchromatography using gradient of 3% MeOH/DCM and further purified byprep HPLC to afford the title compound (5 mg, 4%) as an off-white solid.TLC: 10% MeOH/DCM (Rf: 0.40). (See Table 1 for analytical data).

Synthesis of2-methoxy-N-(4-methoxy-6-((4-(phenylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 50 (100 mg, 0.208 mmol) in DCM (3 mL)at 0° C. was added TEA (0.087 mL, 0.625 mmol) followed bybenzenesulfonyl chloride (44 mg, 0.249 mmol). The reaction was stirredat room temperature for 4 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure to get a browngummy crude. The crude was purified through combi-flash chromatographyusing gradient of 3% MeOH/DCM and further purified by prep HPLC toafford the title compound (5 mg, 4%) as an off-white solid. TLC: 10%MeOH/DCM (Rf: 0.40). (See Table 1 for analytical data).

Synthesis of 3,4,5-trifluoro-N-((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamido) benzo[d]isozolol-6-yl) methyl)-1H-pyrazol-4-yl) methyl)benzenesulfonamide

To a stirred solution of compound 50 (100 mg, 0.104 mmol) in DCM (3 mL)at 0° C. was added TEA (0.044 mL, 0.312 mmol) followed by3,4,5-trifluorobenzenesulfonyl chloride (28 mg, 0.124 mmol). Thereaction was allowed to stir at the room temperature for 4 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure, to get brown gummy crude. The crude was purifiedthrough combi-flash chromatography using gradient of 3% MeOH/DCM andfurther purified by prep HPLC to afford the title compound (16 mg,20.27%) as an off-white solid. TLC: 10% MeOH/DCM (Rf: 0.40). (See Table1 for analytical data).

Synthetic Example 81

Synthesis of5-ethyl-2-methoxy-N-(4-methoxy-6-((4-(vinylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 151 (0.1 g, 0.196 mmol) in DMF (1 mL)at 0° C. was added TEA (0.082 mL, 0.590 mmol) followed by ethenesulfonyl chloride (29 mg, 0.235 mmol). The reaction was allowed to stirat room temperature for 2 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure to get a browngummy crude. The crude was purified by combi-flash chromatography usinggradient of 5%-10% and further purified by prep HPLC to afford the titlecompound (10 mg, 9.09%) as an off-white solid. TLC: 10% MeOH/DCM (Rf:0.40). (See Table 1 for analytical data)

Synthetic Example 82

To a stirred solution of compound 54 (110 mg, 0.241 mmol) in DMF (1 mL)at 0° C. was added TEA (0.101 mL, 0.724 mmol), followed by2,3,4,5,6-pentafluorobenzenesulfonyl chloride (77 mg, 0.289 mmol). Thereaction was allowed to stir at the room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure to get a brown gummy crude. The crude was passedthrough combi-flash chromatography using gradient of 5% MeOH/DCM andfurther purified by prep HPLC to afford the title compound (7 mg, 4.24%)as an off-white solid. TLC: 10% MeOH/DCM (Rf: 0.40). (See Table 1 foranalytical data).

Synthetic Example 83 AND 84

6-chloro-N-((1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)pyridine-3-sulfonamide

To a stirred solution of compound 50 (180 mg, 1.00 mmol) in DCM (2 mL)at 0° C. was added TEA (0.42 mL, 3.00 mmol) and followed by6-chloropyridine-3-sulfonyl chloride (424 mg, 2.00 mmol). The reactionwas allowed to stir at the room temperature for 2 h. After completion(monitored by TLC), the mixture was concentrated under reduced pressure,to get a brown gummy solid which was passed through combi-flashchromatography gradient using 3% MeOH/DCM, then further purified by prepHPLC to afford the title compound (26 mg, 11.11%) as an off-white solid.TLC: 10% MeOH/DCM (Rf: 0.40). (See Table 1 for analytical data).

Synthesis of2-chloro-N-((1((4methoxy3((2methoxyphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl) methyl) pyridine-3-sulfonamide

Using the protocol described above for Syn. Ex. 83, Compound 50 (100 mg,0.208 mmol) was converted to the title compound (12 mg, 9.37%) which wasisolated as an off-white solid. TLC: 10% MeOH/DCM (Rf: 0.40). (See Table1 for analytical data).

Synthetic Example 85

Synthesis of methyl 3-(N-(6-((4-(((tert-butoxycarbonyl)amino)methyl)-lH-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-4-methoxybenzoate(165)

To a stirred solution of compound 17 (1.0 g, 2.678 mmol) in THF (10 mL)at 0° C. was added 1M solution in THF of KO^(t)Bu (0.60 g, 5.356 mmol)followed by methyl 3-(chlorosulfonyl)-4-methoxybenzoate (1.41 g, 5.356mmol) and the reaction was allowed to stir at 0° C. for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The crude compound was purified by combi flash columnchromatography using a gradient method of 40-100% EtOAc/Heptane toafford the title compound 165 (0.650 g, 40.37%) as a brown solid. TLC:70% EtOAc/Heptane (R_(f). 0.38). LCMS Calculated for: C27H31N5O9S:601.18; Found: 602.2 (M+1).

Synthesis of 3-(N-(6-((4-(((tert-butoxycarbonyl) amino)methyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-4-methoxybenzoicacid (166)

To a stirred solution of compound 165 (0.2 g, 0.332 mmol) in a mixtureof (2:1) THF: H₂O (3 mL) was added LiOH·H₂O (27 mg, 0.66 mmol). Thereaction mixture was stirred at the room temperature for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure. The residue was neutralized with 1N HCl andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford the title compound 166 (170 mg, 87.17%) as an off-white solid.TLC: 100% EtOAc/Heptane (R_(f). 0.3); LCMS Calculated for:C26H29N5O9S:587.17; Found: 588.50[M+1].

Synthesis of tert-butyl((1-((4-methoxy-3-((2-methoxy-5-(methylcarbamoyl)phenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(167)

To a stirred solution of compound 166 (170 mg, 0.289 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.155 mL, 0.867 mmol), methyl amine solution,1M in THF (1.1 mL, 1.156 mmol) followed by T₃P as a 50% solution inEtOAc (0.275 mL, 0.433 mmol). The reaction mixture was allowed to stirat room temperature for 4 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure and the crudewas purified by combi flash chromatography using gradient 0-30%EtOAc/Heptane to afford the title 167 (140 mg, 80.9%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). LCMS Calculated for: C27H32N6O8S:600.20; Found: 601.50 [M+1].

Synthesis of 3-(N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)sulfamoyl)-4-methoxy-N-methylbenzamide hydrochloride (168)

To a stirred solution of compound 167 (140 mg, 0.233 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in 1,4 Dioxane (0.29 mL, 1.165 mmol) and thereaction was allowed to stir at room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure and co-evaporated with ether two times to affordthe title compound 168 (100 mg, salt) as a white solid. TLC: 5% MeOH/DCM(Rf: 0.2). This was used in the next step without furthercharacterization.

Synthesis of4-methoxy-3-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl) benzo[d]isoxazol-3-yl)sulfamoyl)-N-methylbenzamide

To a stirred solution of compound 168 (100 mg, 0.280 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.146 mL, 0.840 mmol), propiolic acid (21 mg,0.308 mmol) followed by T₃P as a 50% solution in EtOAc (0.267 mL, 0.42mmol). The reaction mixture was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by prepHPLC to afford the title compound (8 mg, 7.9%) as an off-white solid.TLC: 5% MeOH/DCM (Rf: 0.6). (See Table 1 for analytical data).

Synthetic Example 86

Synthesis of4-methoxy-3-(N-(4-methoxy-6-((4-(((2,2,2-trifluoroacetyl)-14-azaneyl)methyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)sulfamoyl)benzoicacid (169)

To a stirred solution of compound 166 (100 mg, 0.170 mmol) in DCM (2 mL)at 0° C., TFA (0.138 mL, 1.701 mmol) was added at 0° C. and the reactionwas allowed to stir at room temperature for 2 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure, triturated with diethyl ether to afford the title compound 169(70 mg, salt) as a gummy white solid. TLC: 5% MeOH/DCM (Rf: 0.2). Thiswas used in the next step without further characterization. Synthesis of4-methoxy-3-(N-(4-methoxy-6-((4-(propiolamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)sulfamoyl)benzoicacid

To a stirred solution of compound 169 (70 mg, 0.119 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.062 mL, 0.359 mmol), propiolic acid (9 mg,0.130 mmol) followed by T₃P as a 50% solution in EtOAc (0.113 mL, 0.178mmol) and the reaction mixture was allowed to stir at room temperaturefor 16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by prepHPLC to afford the title compound (10 mg, 10.8%) as an off-white solid.TLC: 5% MeOH/DCM (Rf: 0.5). (See Table 1 for analytical data).

Synthetic Example 87

Synthesis of tert-butyl3-(3-bromophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (170)

To a stirred solution of 157 (500 mg, 1.693 mmol) and1-bromo-3-iodobenzene (575 mg, 2.032 mmol) in a 2:1 mixture of 1,4Dioxane:water (9 mL), was added K₂CO₃ (0.701 g, 5.079 mmol) the reactionmixture was degassed with Argon followed by addition of Pd(dppf)Cl₂ (136mg, 0.169 mmol). The reaction mixture was stirred at 80° C. for 16 h.After completion (monitored by TLC), the reaction mixture was filteredon a Celite pad and washed with ethyl acetate and concentrated underreduced pressure. The crude was purified by combi flash-chromatographyusing a gradient method of 0-30% EtOAc/Heptane to afford the titlecompound 170 (700 mg; crude) as a pale brown solid. TLC: 50%EtOAc/Heptane (Rf: 0.4). LCMS Calculated for C15H18BrNO2: 323.05; Found:324.05 (M+1).

Synthesis of tert-butyl3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate(171)

To a stirred solution of 170 (400 mg, 1.233 mmol) in 3:1 mixture of 1,4Dioxane: water (40 mL) was added KOAc (242 mg, 2.46 mmol) followed byBpin₂ (344 mg, 1.356 mmol). The reaction mixture was degassed with argongas for 10 min. followed by addition of Pd(PPh₃)4 (142 mg, 0.12 mmol).The reaction mixture was stirred at 90° C. for 16 h. After completion(monitored by TLC), the reaction mixture was filtered through a pad ofCelite and washed with EtOAC. The filtrate was concentrated underreduced pressure to afford the title compound 171 (480 mg, crude) as ayellow solid. TLC: 50% EtOAc/Heptane (R_(f). 0.5). LCMS Calculated forC21H30BNO4: 371.23; Found: 372.02 (M+1).

Synthesis of tert-butyl3-(3-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)phenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate(172)

To a stirred solution of compound 117 (200 mg, 0.451 mmol) in 3:1mixture of 1,4 Dioxane: water (4 mL) was added K₂CO₃(124 mg, 0.902 mmol)followed by compound 171 (184 mg, 0,496 mmol). The reaction mixture wasallowed to stir at 80° C. for 16 h. After completion (monitored by TLC),the reaction mixture was cooled to room temperature, quenched with icewater and extracted with ethyl acetate. The organic layer was dried overanhydrous Na₂SO₄, and concentrated under reduced pressure. The crudecompound was purified by combi flash chromatography (neutral alumina) toafford the title compound 172 (180 mg, crude), as an off-white solid.TLC: 50% EtOAc/Heptane (R_(f). 0.6). LCMS Calculated for C31H33N3O8S:607.20; Found:608.5 (M+1).

Synthesis of tert-butyl3-(3-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)phenyl)pyrrolidine-1-carboxylate(173)

An autoclave was charged with a solution of Compound 172 (150 mg 0.246mmol) in MeOH:EtOAc (15 mL, 2:1), TEA (0.069, 0.493 mmol) and themixture was purged with nitrogen for 5 min. followed by addition of 10%Pd/C (52 mg). The reaction mixture was allowed to stir under hydrogenatmosphere (60 psi) at room temperature for 16 h. After completion(monitored by TLC), the reaction mixture was filtered through a pad ofCelite and washed with MeOH. The filtrate was concentrated under reducedpressure. The crude product was purified by Combi flash chromatography(using a gradient method of 0-5% MeOH/DCM) to afford the title compound173 (200 mg, crude) as a white solid. TLC: 50% EtOAc/Heptane (R_(f).0.6). LCMS Calculated for C31H35N3O8S: 609.21; Found: 610.08 (M+1).

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(3-(1-(2,2,2-trifluoroacetyl)-114-pyrrolidin-3-yl)phenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(174)

To a stirred solution of compound 173 (200 mg, 0.328 mmol) in DCM (2 mL)was added TFA (0.26 mL, 3.28 mmol) at 0° C. The reaction was allowed tostir at the room temperature for 2 h. After completion (monitored byTLC), the reaction mixture was concentrated under reduced pressure andco-evaporated with toluene to afford the title compound 174 (190 mg,salt,) as a thick brown oil. TLC: 5% MeOH/DCM (R_(f). 0.3). The crudematerial was used for the next step without any purification.

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(3-(1-propioloylpyrrolidin-3-yl)phenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 174 (90 mg, 0.148 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.103 mL, 0.593 mmol) and propiolic acid (12mg, 0.177 mmol) followed by T₃P as a 50% solution in EtOAc (0.141 mL,0.222 mmol). The reaction mixture was allowed to stir at roomtemperature for 16 h. After completion (monitored by TLC), the reactionmixture was concentrated under reduced pressure and the crude waspurified by prep HPLC to afford the title compound (4 mg, 4.81%) as anoff-white solid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 foranalytical data).

Synthetic Example 88

Synthesis of tert-butyl(2-((4-cyano-3-fluoro-5-methoxybenzyl)oxy)ethyl)carbamate (175)

To a stirred solution of compound 87 (250 mg, 1.024 mmol) in ACN (5 mL)was added K₂CO₃ (283 mg, 2.048 mmol) followed by tert-butyl(2-hydroxyethyl)carbamate (54 mg, 0.339 mmol). The reaction mixture wasstirred at 80° C. for 16 h. After completion (monitored by TLC), thereaction mixture was cooled to room temperature, quenched with ice coldwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by combi flash chromatography(using a gradient method of 0-30% EtOAc/Heptane) to afford the titlecompound 175 (300 mg, 90.36%) as a yellow solid. TLC: 50% EtOAc/Heptane(Rf: 0.5). LCMS Calculated for C16H21FN2O4: 324.15; Found: 325.5 (M+H).

Synthesis of tert-butyl(2-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methoxy)ethyl)carbamate(176)

To a stirred solution of compound 175 (300 mg, 0.924 mmol) in a 6:1mixture of DMF: H₂O (7 mL) at room temperature was addedN-hydroxyacetamide (208 mg, 2.774 mmol) followed by K₂CO₃ (0.766 g,5.544 mmol). The reaction mixture was allowed to stir at 60° C. for 16h. After completion (monitored by TLC), the reaction mixture was cooledto room temperature, quenched with ice cold water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by combi flash chromatography using a gradientmethod of 50-90% EtOAc/Heptane to afford the title compound 176 (250 mg,80.12%) as a colorless gummy oil. TLC: 80% EtOAc/Heptane (R_(f). 0.40).LCMS Calculated for C16H23N3O5: 337.16; Found: 338.02 (M+1).

Synthesis of tert-butyl(2-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methoxy)ethyl)carbamate(177)

To a stirred solution of compound 176 (120 mg, 0.355 mmol) in THF (5 mL)at 0° C. was added Na^(t)OPn (195 mg, 1.775 mmol) followed by5-ethyl-2-methoxybenzenesulfonyl chloride (166 mg, 0.711 mmol). Thereaction was allowed to stir at 60° C. for 6 h. After completion(monitored by TLC), the reaction mixture was quenched with water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude compound was purified by combi flash column chromatographyusing a gradient method of 20-60% EtOAc/Heptane to afford the titlecompound 177 (180 mg, 94.73%) as an off-white solid. TLC: 80% EtOAc(R_(f). 0.5). LCMS Calculated for: C25H33N3O8S: 535.20; Found: 536.5(M+1).

Synthesis ofN-(6-((2-aminoethoxy)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamidehydrochloride (178)

To a stirred solution of compound 177 (0.15 g, 0.26 mmol) in DCM (1 mL)was added 4M HCl in Dioxane (1 mL) at 0° C. The reaction was allowed tostir at the room temperature for 2 h. After completion (monitored byTLC), the reaction mixture was concentrated under reduced pressure andwashed with diethyl ether and heptane to afford the title compound 178(115 mg, HCl salt) as a yellow solid. TLC: 10% MeOH/DCM (Rf: 0.5).

The crude material was used for the next step without any purification.

Synthesis ofN-(2-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methoxy)ethyl)propiolamide

To a stirred solution of compound 178 (115 mg, 0.243 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.127 mL, 0.729 mmol) followed by T₃P as a 50%solution in ethyl acetate (0.231 mL, 0.364 mmol). The reaction wasallowed to stir at the room temperature for 50 min. After that, apre-dissolved solution of propiolic acid (34 mg, 0.486 mmol) in DMF (0.3mL) was added dropwise and the reaction was allowed to stir at the roomtemperature for 4 h. After completion (monitored by TLC), the reactionmixture was quenched with water and extracted with Ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The crude compound was purified byusing prep HPLC to afford the title compound (11.4 mg, 9.66%) as anoff-white solid. TLC: 10% MeOH/DCM (Rf: 0.5). (See Table 1 foranalytical data)

Synthetic Example 89 AND 90

Synthesis of tert-butyl(3-((4-cyano-3-fluoro-5-methoxybenzyl)oxy)propyl)carbamate (179)

To a stirred solution of compound 87 (1.5 g, 6.146 mmol) in ACN (20 mL)was added K₂CO₃ (1.7 g, 12.292 mmol) at 0° C. and stirred for 15 min.After, tert-butyl (3-hydroxypropyl) carbamate (1.34 g, 6.93 mmol) wasadded, and the reaction was allowed to stir at the room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasquenched with ice cold water and extracted with ethyl acetate. Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The crude compound was purified by silica gel[100-200 mesh] column chromatography to afford the title compound 179(1.2 g, 57.97%) as a white solid. TLC: 5% MeOH/DCM (Rf. 0.2); LCMSCalculated for C17H23FN2O4: 338.16; Found: 339.15 (M+1).

Synthesis of tert-butyl (3-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methoxy) propyl) carbamate (180)

To a stirred solution of compound 179 (1.2 g, 3.546 mmol) in a 6:1mixture of DMF: H₂O (7 mL) at room temperature was addedN-hydroxyacetamide (0.399 g, 5.319 mmol) followed by K₂CO₃ (1.47 g,10.638 mmol). The reaction mixture was allowed to stir at 60° C. for 16h. After completion (monitored by TLC), the reaction mixture wasquenched with ice cold water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to offer the title 180 (800 mg,64.20%) as a brown semi-solid. TLC: 70% EtOAc/Heptane (Rf: 0.40). LCMSCalculated for C17H25N3O5: 351.18; Found: 352.02 (M+1).

Synthesis of tert-butyl (3-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) methoxy) propyl) carbamate(181)

To a stirred solution of compound 180 (0.8 g, 2.276 mmol) in THF (5 mL)at 0° C. was added NaH (60% dispersion in mineral oil, 0.273 mg, 6.829mmol) followed by 5-ethyl-2-methoxybenzenesulfonyl chloride (640 mg,2.731 mmol). The reaction was allowed to stir at 60° C. for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude was purified by combi flash using gradient 0-50%EA/Heptane to afford the title compound 181 (900 mg, 72%) as acolourless gummy solid. TLC: 50% EtOAc (R_(f). 0.5). LCMS Calculated forC26H35N3O8S: 549.21; Found: 550.02 (M+1).

Synthesis of N-(6-((3-aminopropoxy)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamidehydrochloride (182)

To a stirred solution of compound 181 (900 mg, 1.637 mmol) in DCM (4 mL)was added 4M HCl in dioxane (4 mL, 16.374 mmol) at 0° C. The reactionwas allowed to stir at the room temperature for 2 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure. The crude compound was triturated with diethyl ether (20 mL)to afford the title compound 182 (500 mg, HCl salt) as a yellow solid.TLC: 10% MeOH/DCM (R_(f). 0.3). The crude material was used in the nextstep without any purification.

Synthesis of N-(3-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) methoxy) propyl)propiolamide

To a stirred solution of compound 182 (500 mg, 1.028 mmol) in DMF (5 mL)at 0° C. was added DIPEA (0.54 mL, 3.086 mmol), propiolic acid (86 mg,1.233 mmol) followed by T₃P as a 50% solution in EtOAc (0.98 mL, 1.542mmol). The reaction mixture was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. The crude was purified by usingprep HPLC to afford the title compound (47 mg, 9.1%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthesis of 5-ethyl-2-methoxy-N-(4-methoxy-6-((3-(vinylsulfonamido)propoxy) methyl) benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 182 (300 mg, 0.617 mmol) in DMF (1 mL)at 0° C. was added TEA (0.173 mL, 1.234 mmol) followed by ethenesulfonylchloride (0.23 mg, 1.851 mmol). The reaction mixture was allowed to stirat 0° C. for 1 h. After completion (monitored by TLC), the reactionmixture was quenched with ice cold water and extracted with EtOAc. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The crude was purified by usingprep HPLC to afford the title compound (24 mg, 7.20%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 91

Synthesis of (4-bromo-6-methylpyridin-2-yl)methanol (184)

To a stirred solution of compound 183 (5 g, 29.064 mmol) in MeOH (90 mL)at 0° C. was added H₂SO₄ (25 mL) and reaction was allowed to stir at 80°C. for 1 h. A premixed solution of ammonium persulfate (166 mg, 87.192mmol) in H₂O was added in the reaction mixture. The reaction was allowedto stir at 80° C. for 16 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure and extractedwith Ethyl Acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure. The crudecompound was purified by combi flash column chromatography using agradient method of 20-60% EtOAc/Heptane to afford the title compound 184(800 mg, 13.62%) as an off-white solid. TLC: 80% EtOAc (R_(f). 0.5).LCMS Calculated for: C7H8BrNO: 200.95; Found: 201.5 (M+1).

Synthesis of 4-bromo-6-methylpicolinic acid (185)

To a stirred solution of 184 (3.4 g, 19.76 mmol) in ACN (27 mL) andwater (37 mL) was added KMnO₄ (7.93 g, 50.200 mmol). The reactionmixture was stirred at 40° C. for 2 h. After completion (monitored byTLC), the reaction mixture was concentrated under reduced pressure. Thecrude was purified by using prep HPLC to afford the title compound 185(3.6 g, 85%) as an off-white solid. TLC: 10% MeOH/DCM (R_(f). 0.5). LCMSCalculated for C7H6BrNO2: 214.96; Found: 216.1 (M+2). The crude compoundwas used to the next step without purification.

Synthesis of methyl 4-bromo-6-methylpicolinate (186)

To a stirred solution of 4-bromo-6-methyl-pyridine-2-carboxylic acid 185(3.6 g, 16.66 mmol) in methanol (75 mL, 1850 mmol) was added H₂SO₄ (8.16mL, 83.3 mmol) and water (1.8 mL). The reaction mixture was stirred at75° C. for 16 h. After completion (monitored by TLC), the reactionmixture was concentrated under reduced pressure to get crude. The crudewas quenched with saturated sodium bicarbonate solution and wasextracted with ethyl acetate. The combined organic layer was dried oversodium sulphate and filtered and concentrated under reduced pressure toget crude. The crude was purified by combi flash chromatography usinggradient 11% EA/Heptane to offer title compound 186 (1.4 g, 36.84%) as awhite solid. TLC: 10% MeOH/DCM (R_(f). 0.5). LCMS Calculated forC8H8BrNO2: 228.97; Found: 229.5 (M+1).

Synthesis of methyl4-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)-6-methylpicolinate(187)

To a stirred solution of methyl 4-bromo-6-methyl-pyridine-2-carboxylate186 (500 mg, 2.173 mmol) in Toluene (8 mL) was added tert-butyl((1H-pyrazol-4-yl)methyl)carbamate (557 mg, 2.825 mmol) and K₂CO₃ (900mg, 6.519 mmol). The reaction mixture was purged with nitrogen for 10min followed by addition of Copper(I) iodide (82 mg, 0.434 mmol) andtrans-N,N-dimethylcyclohexane-1,2-diamine (61 mg, 0.43467 mmol). Thereaction mixture was stirred at 150° C. for 2 h under microwaveirradiation. After completion (monitored by TLC), the reaction wasquenched with ice cold water and extracted with ethyl acetate. Thecombined organic layer was washed with brine solution, dried over sodiumsulphate filtered and concentrated under reduced pressure to get crudecompound. The crude was purified by combiflash chromatography usinggradient 55% EA/Heptane to offer the title compound 187 (307 mg, 40.82%)as a brown semi solid. LCMS Calculated for C17H22N4O4: 346.16; Found:347.3 (M+1).

Synthesis of tert-butyl((1-(2-(hydrazinecarbonyl)-6-methylpyridin-4-yl)-1H-pyrazol-4-yl)methyl)carbamate(188)

To a stirred of compound 187 (135 mg, 0.3897 mmol) in EtOH (5 mL), wasadded NH₂NH₂·H₂O (0.2 mL). The reaction mixture was stirred at 85° C.for 16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure to get crude. The crude wastriturated with DCM/Pentane (20 mL, 1:9 ratio) to offer title compound188 (120 mg, 88.88% yield) as a brown solid. This was used in the nextstep without further characterization.

Synthesis of tert-butyl((1-(2-(2-((2-fluorophenyl)sulfonyl)hydrazine-1-carbonyl)-6-methylpyridin-4-yl)-1H-pyrazol-4-yl)methyl)carbamate(189)

To a stirred of compound 188 (110 mg, 0.3176 mmol) in THF (1.0 mL) andpyridine (1.0 mL) was added 2-fluorobenzenesulfonyl chloride (123 mg,0.6351 mmol). The reaction mixture was stirred at room temperature for 3h. After completion (monitored by TLC), the reaction mixture wasquenched with 1N HCl and was extracted with ethyl acetate. The organiclayer was washed with brine solution, dried over sodium sulphatefiltered and concentrated under reduced pressure. The crude was purifiedby combi flash column chromatography using gradient 75-90% EA/Heptane tooffer title compound 189 (100 mg, 62.5%) as a brown solid. TLC: 10%MeOH/DCM (R_(f). 0.3). LCMS Calculated for: C22H25FN6O5S: 504.16; Found:505.7 (M+1).

Synthesis ofN′-(4-(4-(aminomethyl)-1H-pyrazol-1-yl)-6-methylpicolinoyl)-2-fluorobenzenesulfonohydrazidehydrochloride (190)

To a stirred solution of compound 189 (90 mg, 0.1784 mmol) in DCM (3 mL)was added 4M HCl in Dioxane (0.44 mL, 1.784 mmol). The reaction mixturewas stirred at RT for 2 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure. The crude wastriturated with 1:9 ratio of DCM/n-pentane to offer the title compound190 (70 mg, 0.167 mmol, 93.8% Yield) as a brown solid. This was used inthe next step without further characterization. Synthesis ofN-((1-(2-(2-((2-fluorophenyl) sulfonyl)hydrazine-1-carbonyl)-6-methylpyridin-4-yl)-1H-pyrazol-4-yl) methyl)propiolamide

To a stirred solution of compound 190 (70 mg, 0.158 mmol) in DMF (4 mL)was added DIPEA (0.083 mL, 0.476 mmol), propiolic acid (13 mg, 0.189mmol) followed by T₃P as a 50% solution in EtOAc (0.603 mL, 0.948 mmol)at 0° C. The reaction mixture was stirred at RT for 2 h. Aftercompletion (monitored by TLC), reaction mixture was quenched with icecold water and extracted with ethyl acetate. The organic layer was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by using prep HPLC to afford the title compound(4.3 mg, 4.1%) as a brown gummy solid. TLC: 10% MeOH/DCM (R_(f). 0.4).(See Table 1 for analytical data).

Synthetic Example 92

Synthesis of tert-butyl3-(2-chloropyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (191)

To a stirred solution of compound 71 (400 mg, 2.078 mmol) in 3:1 mixtureof 1,4 Dioxane: water (10 mL) was added K₂CO₃ (862 mg, 6.235 mmol) andtert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(736 mg, 2.49 mmol). The reaction mixture was purged under nitrogenatmosphere followed by addition of Pd(PPh₃)4 (0.120 g, 0.1039 mmol). Thereaction mixture was stirred at 100° C. for 16 h. After completion(monitored by TLC), the reaction mixture was filtered through a pad ofcelite, diluted with water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycombi flash chromatography (using a gradient method of 0-30%EtOAc/Heptane) to afford the title compound 191 (350 mg, 60%) as ayellow solid. TLC: 50% EtOAc/Heptane (R_(f). 0.5). LCMS Calculated forC14H17ClN2O2: 280.10; Found: 281.5 (M+H).

Synthesis of tert-butyl3-(2-(3-(methoxycarbonyl)-5-methylphenyl)pyridin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(192)

To a stirred solution of compound 191 (350 mg, 1.246 mmol) in 3:1mixture of 1,4 Dioxane: water (40 mL) was added K₂CO₃ (517 mg, 3.73mmol) and methyl3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (412mg, 1.495 mmol). The reaction mixture was purged under nitrogenatmosphere followed by addition of Pd(PPh₃)4 (71 mg, 0.0623 mmol). Theresulting reaction mixture was stirred at 90° C. for 12 h. Aftercompletion (monitored by TLC), the reaction mixture was filtered througha pad of celite, diluted with water and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycombi flash chromatography (using a gradient method of 0-50%EtOAc/Heptane) to afford the title compound 192 (394 mg, 80.24%) as apale-yellow solid. TLC: 50% EtOAc/Heptane (R_(f). 0.5). LCMS Calculatedfor C23H26N2O4: 394.19; Found: 395.5 (M+1)

Synthesis of tert-butyl3-(2-(3-(methoxycarbonyl)-5-methylphenyl)pyridin-4-yl)pyrrolidine-1-carboxylate(193)

An autoclave was charged with a solution of Compound 192 (280 mg 0.709mmol) in MeOH (15 mL) and the mixture was degassed with nitrogenatmosphere three times followed by addition of 10% Pd/C (50 mg). Thereaction mixture was purged with hydrogen gas and was allowed to stirunder hydrogen atmosphere (100 psi) at room temperature for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was filtered througha pad of Celite and washed with MeOH. The filtrate was concentratedunder reduced pressure to the dryness. The crude product was purified bycombi flash chromatography (using a gradient method of 0-5% MeOH/DCM) toafford the desired title compound 193 (250 mg, crude) as a white solid.TLC: 50% EtOAc/Heptane (R_(f). 0.6). LCMS Calculated for C23H28N2O4:396.20; Found: 397.08 (M+1).

Synthesis of tert-butyl3-(2-(3-(hydrazinecarbonyl)-5-methylphenyl)pyridin-4-yl)pyrrolidine-1-carboxylate(194)

To a stirred solution of compound 193 (0.3g, 0.756 mmol) in EtOH (20 mL)was added hydrazine hydrate (0.22 mL, 4.539 mmol) and the reaction wasallowed to stir at 80° C. for 16 h. After completion (monitored by TLC),the reaction mixture was concentrated under reduced pressure. The crudewas triturated with DCM/n-Heptane and concentrated under reducedpressure to afford the title compound 194 (200 mg, 66.66%) as apale-yellow solid. TLC: 5% MeOH/DCM (R_(f). 0.3). LCMS Calculated forC22H28N4O3: 396.22; Found: 397.01 (M+1).

Synthesis of tert-butyl3-(2-(3-(2-((2-fluorophenyl)sulfonyl)hydrazine-1-carbonyl)-5-methylphenyl)pyridin-4-yl)pyrrolidine-1-carboxylate(195)

To a solution of compound 194 (0.200 g, 0.504 mmol) in DMF (5 mL) at 0°C. was added K₂CO₃ (0.209 g, 1.513 mmol) followed by2-fluorobenzenesulfonyl chloride (0.117 g, 0.604 mmol). The reactionmixture was stirred at 90° C. for 16 h. After completion (monitored byTLC), the reaction mixture was diluted with H₂O and extracted withEtOAc. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by combi flash chromatography (using a gradient method of 0-50%EtOAc/Heptane) to afford the title compound 195 (180 mg, 80.24%) aspale-yellow solid. TLC: 50% EtOAc/Heptane (R_(f). 0.5). LCMS Calculatedfor C28H31FN4O5S: 554.20; Found: 555.5 (M+1)

Synthesis of2-fluoro-N′-(3-methyl-5-(4-(pyrrolidin-3-yl)pyridin-2-yl)benzoyl)benzenesulfonohydrazidehydrochloride (196)

To a stirred solution of compound 195 (180 mg, 0.324 mmol) in DCM (3 mL)at 0° C. was added 4M HCl in dioxane (0.48 mL, 1.94 mmol). The reactionwas allowed to stir at the room temperature for 1 h. After completion ofthe reaction (monitored by TLC), the reaction mixture was concentratedunder reduced pressure. The crude compound was triturated with diethylether to afford the title compound 196 (90 mg, HCl salt) as a brownsolid. TLC: 5% MeOH/DCM (R_(f). 0.5). This was used in the next stepwithout further characterization.

Synthesis of2-fluoro-N′-(3-methyl-5-(4-(1-propioloylpyrrolidin-3-yl)pyridin-2-yl)benzoyl)benzenesulfonohydrazide

To a stirred solution of compound 196 (90 mg, 0.183 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.096 mL, 0.549 mmol), Propiolic acid (15 mg,0.219 mmol) followed by T₃P as a 50% solution in EtOAc (0.174 mL, 0.274mmol). The reaction mixture was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (22 mg, 4.81%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 93

Synthesis of tert-butyl (2-(((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl) amino)-2-oxoethyl) carbamate (197)

To a stirred solution of compound 151 (180 mg, 0.354 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.185 mL, 1.063 mmol), (tert-butoxycarbonyl)glycine (124 mg, 0.708 mmol) followed by T₃P as a 50% solution in EtOAc(0.337 mL, 0.531 mmol). The reaction mixture was stirred at the roomtemperature for 16 h. After completion (monitored by TLC), the reactionmixture was quenched with aqueous ammonium chloride and extracted withethyl acetate. The organic layer was dried over anhydrous Na₂SO₄, toafford the title compound 197 (150 mg, 67.56%) as a pale brown gummysolid. TLC: 10% MeOH/DCM (Rf 0.5). LCMS Calculated for C29H36N6O8S:628.28; Found: 629.5 (M+1).

Synthesis of2-amino-N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)acetamidehydrochloride (198)

To a stirred solution of compound 197 (150 g, 0.238 mmol) in DCM (3 mL)at 0° C. was added 4M HCl in 1,4-dioxane (0.596 mL, 2.385 mmol). Thereaction was allowed to stir at the room temperature for 4 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure and Co distilled with diethyl ether to afford thetitle 198 (150 mg, HCl Salt) as a yellow solid. TLC: 15% MeOH/DCM(R_(f). 0.2); This was used in the next step without furthercharacterization.

Synthesis of N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl)-2-(vinylsulfonamido) acetamide

To a stirred solution of compound 198 (100 mg, 0.176 mmol) in DCM (4 mL)at 0° C. was added TEA (0.074 mL, 0.530 mmol) and ethene sulfonylchloride (22 mg, 0.22 mmol). The reaction mixture was stirred at 0° C.for 4 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. The crude was purified by usingprep HPLC to afford the title compound (9.4 mg, 9.03%) as an off-whitesolid. TLC: 10% MeOH/DCM (R_(f). 0.6). (See Table 1 for analyticaldata).

Synthetic Example 94

Synthesis of1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazole-4-carboxylicacid (199)

To a stirred solution of compound 125 (400 mg, 1.264 mmol) in THF (5 mL)at 0° C. was added NaH as a 60% dispersion in mineral oil (0.101 mg,2.529 mmol) followed by 5-ethyl-2-methoxybenzenesulfonyl chloride (444mg, 1.896 mmol). The reaction was allowed to stir at 60° C. for 16 h.After completion (monitored by TLC), the reaction mixture was quenchedwith ice cold water and acidified the aqueous layer by citric acidaqueous solution to pH ˜ 6. The aqueous layer was extracted with ethylacetate. The organic layer was collected, washed with brine, dried overanhydrous Na₂SO₄, and concentrated under reduced pressure to afford thetitle compound 199 (150 mg, 23.07%) as a colour less gummy solid. TLC:50% EtOAc (R_(f). 0.5). LCMS Calculated for C22H22N4O7S: 486.12; Found:487.02 (M+1).

Synthesis of tert-butyl (2-(1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazole-4-carboxamido) ethyl) carbamate (200)

To a stirred solution of compound 199 (120 mg, 0.246 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.086 mL, 0.493 mmol), tert-butyl(2-aminoethyl)carbamate (39 mg, 0.246 mmol) followed by T₃P as a 50%solution in EtOAc (0.234 mL, 0.369 mmol). The reaction mixture wasallowed to stir at room temperature for 12 h. After completion(monitored by TLC), the reaction mixture was quenched with water andextracted with Ethyl Acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude was purified by combi flash chromatography using gradient20-50% EA/Heptane to afford the title compound 200 (90 mg, 58.06%) as anoff-white solid. TLC: 5% MeOH/DCM (R_(f). 0.5). LCMS Calculated forC29H36N6O8S: 628.23; Found: 629.02 (M+1).

Synthesis of N-(2-aminoethyl)-1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazole-4-carboxamide hydrochloride (201)

To a stirred solution of compound 200 (90 mg, 0.143 mmol) in DCM (3 mL)at 0° C. was added 4M HCl in Dioxane (0.35 mL, 1.431 mmol). The reactionmixture was allowed to stir at room temperature for 4 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure. The crude was triturated with Diethylether/Heptane to afford the title compound 201 (62 mg, 77.5%) as anoff-white gummy solid. TLC: 5% MeOH/DCM (R_(f). 0.2). This was used inthe next step without further characterization.

Synthesis of 1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-N-(2-propiolamidoethyl)-1H-pyrazole-4-carboxamide

To a stirred solution of compound 201 (62 mg, 0.109 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.038 mL, 0.218 mmol), Propiolic acid (15 mg,0.218 mmol) followed by T₃P as a 50% solution in EtOAc (0.138 mL, 0.218mmol). The reaction mixture was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. The crude was purified by usingprep HPLC to afford the title compound (14.8 mg, 4.81%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 95

Synthesis of tert-butyl4-(1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazole-4-carbonyl)piperazine-1-carboxylate(202)

To a stirred solution of Boc-piperazine (128 mg, 0.690 mmol) in DMF (1mL) at 0° C. was added DIPEA (0.3 mL, 1.725 mmol), compound 199 (280 mg,0.575 mmol) followed by T₃P as a 50 solution in EtOAc (0.548 mL, 0.862mmol). The reaction mixture was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound 202 (120 mg, 31.910%) as a brownliquid. TLC: 500 MeOH/DCM (Rf. 0.5). LCMS Calculated for C31H38N₆O₈S:654.28; Found: 655.21

Synthesis of5-ethyl-2-methoxy-N-(4-methoxy-6-((4-(piperazine-1-carbonyl)-1H-pyrazol-1-yl)methyl)benzo[id]isoxazol-3-yl)benzenesulfonamidehydrochloride (203)

To a stirred solution of compound 202 (100 mg, 0.152 mmol) in DCM (3 mL)at 0° C. was added 4M HCl in dioxane (0.38 mL, 1.527 mmol). The reactionwas allowed to stir at the room temperature for 5 h. After completion(monitored by TLC), concentrated under reduced pressure and the crudecompound was triturated with diethyl ether to afford the title compound203 (70 mg, HCl salt) as pale-yellow solid. TLC: 50% EA/Heptane (Rf.0.2). This was used in the next step without further characterization.

Synthesis of5-ethyl-2-methoxy-N-(4-methoxy-6-((4-(4-propioloylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 203 (70 mg, 0.188 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.062 mL, 0.355 mmol), Propiolic acid (15 mg,0.225 mmol) followed by T₃P as a 50% solution in EtOAc (0.179 mL, 0.282mmol). The reaction mixture was allowed to stir at room temperature for6 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (41 mg, 41.84%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 96

Synthesis of (3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) boronic acid (204)

To a stirred solution of compound 117 (1 g, 2.255 mmol) in DMSO (3 mL)at room temperature was added B₂pin₂ (1.71 g, 6.765 mmol) and KOAc(0.663 mg, 6.765 mmol). The reaction mixture was degassed with nitrogenatmosphere for 10 min, followed by addition ofbis(triphenylphosphine)palladium chloride (79 mg, 0.112 mmol). Thereaction mixture was stirred at 90° C. for 12 h. After completion(monitored by TLC), the reaction mixture was quenched with ice coldwater, filtered through a pad of celite and filtrate was extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by using combi flash chromatography using agradient method of 0-30% EtOAc/Heptane to afford the title compound 204(800 mg, 86.95%) as a pale-yellow solid. TLC: 50% EtOAc/Heptane (Rf0.5). LCMS Calculated for C16H17BN₂O8S: 408.08; Found: 409.5 and 491.6(M+1). (mixture of boronic acid and ester).

Synthesis of tert-butyl 4-(6-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)pyridin-2-yl)piperazine-1-carboxylate(205)

To a stirred solution of tert-butyl4-(6-bromopyridin-2-yl)piperazine-1-carboxylate (1.0 g, 2.939 mmol) in1,4-dioxane:H₂O (5:1, 12 mL) was added compound 204 (0.8 g, 1.959 mmol)followed by the addition of K₂CO₃ (0.812 g, 5.877 mmol) and purged withargon gas for 15 min. PdCl₂(dppf) (71 mg, 0.0959 mmol) and XPhos (45 mg,0.0959 mmol) were added to the reaction mixture and purged with argonfor 5 min. The reaction mixture was heated at 80° C. for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was diluted with H₂Oand extracted with EtOAc. The combined organic layer was washed withbrine solution, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude was purified by combi-flash chromatographyusing gradient 0-35% EtOAc/hexanes to afford title compound 205 (500 mg,40.98%) as an off-white solid, TLC: 50% EA/Heptane (R_(f). 0.2). LCMSCalculated for C30H35N5O8S: 625.22; Found: 626.5

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(6-(piperazin-1-yl)pyridin-2-yl)benzo[d]isoxazol-3-yl)benzenesulfonamidehydrochloride (206)

To a stirred solution of compound 205 (500 mg, 0.799 mmol) in DCM (3 mL)at 0° C. was added 4M HCl in dioxane (2 mL, 7.991 mmol). The reactionwas allowed to stir at room temperature for 5 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure and the crude compound was triturated with diethyl ether toafford the title compound 206 (350 mg, HCl salt) as a colourless semisolid. TLC: 50% MeOH/DCM (R_(f). 0.2). This was used in the next stepwithout further characterization. Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(6-(4-propioloylpiperazin-1-yl)pyridin-2-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 206 (200 mg, 0.355 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.186 mL, 1.067 mmol), Propiolic acid (29 mg,0.426 mmol) followed by T₃P as a 50% solution in EtOAc (0.338 mL, 0.532mmol). The reaction mixture was allowed to stir at room temperature for4 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (8 mg, 3.9%) as a brown solid.TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 97

Synthesis of tert-butyl 4-(4-bromothiazol-2-yl) piperazine-1-carboxylate(210)

To a stirred solution of compound 209 (1 g, 4.116 mmol) in DMF (10 mL)at 0° C. was added TEA (1.15 mL, 8.233 mmol) followed by tert-butylpiperazine-1-carboxylate (0.766 mg, 4.116 mmol). The reaction mixturewas allowed to stir at 60° C. for 16 h. After completion (monitored byTLC), the reaction mixture was quenched with ice cold water andextracted with EtOAc. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Thecrude was purified by using trituration with diethyl ether/pentane toafford the title compound 210 (900 mg, 74%) as an off-white solid.TLC:5% MeOH/DCM (R_(f). 0.5)

Synthesis of tert-butyl 4-(4-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) thiazol-2-yl)piperazine-1-carboxylate (207)

To a stirred solution of compound 210 (500 mg, 1.435 mmol) in 3:1mixture of 1,4 Dioxane: water (4:1, 10 mL) was added K₂CO₃ (595 mg,4.305 mmol) and comp 204 (702 mg, 1.722 mmol). The reaction mixture waspurged with nitrogen gas for 10 min followed by addition of [Pd(PPh₃)₄](0.117 g, 0.143 mmol). The resulting reaction mixture was stirred at 80°C. for 16 h. After completion (monitored by TLC), the reaction mixturewas filtered through a pad of celite. The filtrate was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by combi flash chromatography(using a gradient method of 0-30% EtOAc/Heptane) to afford the titlecompound 207 (0.1 g, 12.93%) as a yellow solid. TLC: 50% EtOAc/Heptane(R_(f). 0.5). LCMS Calculated for C28H33N5O8S2: 631.18; Found: 632.5(M+H).

Synthesis of 2,6-dimethoxy-N-(4-methoxy-6-(2-(piperazin-1-yl)thiazol-4-yl) benzo[d]isoxazol-3-yl) benzenesulfonamide hydrochloride(208)

To a stirred solution of compound 207 (100 mg, 0.158 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in dioxane (0.4 mL, 1.582 mmol). The reactionwas allowed to stir at room temperature for 1 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure and the crude compound was triturated with diethyl ether toafford the title compound 208 (80 mg, HCl salt) as a colourless gummysolid. TLC: 5% MeOH/DCM (R_(f). 0.5). This was used in the next stepwithout further characterization. Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(2-(4-propioloylpiperazin-1-yl)thiazol-4-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 208 (80 mg, 0.140 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.073 mL, 0.422 mmol), Propiolic acid (11 mg,0.168 mmol) followed by T₃P as a 50% solution in EtOAc (0.133 mL, 0.21mmol). The reaction mixture was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by prepHPLC to afford the title compound (20 mg, 24.39%) as an off-white solid.TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 98

Synthesis ofN-(6-bromo-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide(211)

To a stirred solution of compound 116 (800 mg, 3.291 mmol) in THF (10mL) was added KO^(t)Bu as a 1.0 M solution in THF (9.8 mL, 9.874 mmol)followed by 5-ethyl-2-methoxybenzenesulfonyl chloride (1.5 g, 6.582mmol) at 0° C. The reaction mixture was allowed to stir at the roomtemperature for 16 h. After completion (monitored by TLC), the reactionmixture was quenched with ice cold water and extracted with ethylacetate. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was trituratedwith diethyl ether/Heptane to afford the title compound 211 (400 mg,27.58%), as a yellow solid. TLC: 60% EtOAc/Heptane (R_(f). 0.6). LCMSCalculated for C17H17BrN2O5S:440.00; Found:442.5 (M+2).

Synthesis of tert-butyl4-(3-(3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)phenyl)piperazine-1-carboxylate(212)

To a stirred solution of 211 (400 mg, 0.906 mmol) and tert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(386 mg, 0.996 mmol) in a 2:1 mixture of 1,4 Dioxane:water (9 mL) wasadded K₂CO₃ (0.375 g, 2.718 mmol). The reaction mixture was degassedwith Argon atmosphere followed by addition of Pd(dppf)Cl₂ (73 mg, 0.0906mmol). The reaction mixture was stirred at 80° C. for 12 h. Aftercompletion (monitored by TLC), the reaction mixture was diluted withethyl acetate filtered through a Celite pad and the reaction mixture wasconcentrated under reduced pressure. The crude was purified by combiflash-chromatography using a gradient method of 0-30% EtOAc/Heptane toafford the tert-butyl 4-(3-(3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) phenyl)piperazine-1-carboxylate 212 (300 mg, 53.15%) as a pale-yellow solid.TLC: 40% EtOAc/Heptane (R_(f). 0.4). LCMS Calculated for C32H38N4O7S:622.25; Found: 623.02 (M+1).

Synthesis of 5-ethyl-2-methoxy-N-(4-methoxy-6-(3-(piperazin-1-yl)phenyl) benzo[d]isoxazol-3-yl) benzenesulfonamide hydrochloride (213)

To a stirred solution of compound 212 (300 mg, 0.481 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in 1,4 Dioxane (0.24 mL, 0.963 mmol). Thereaction was allowed to stir at the room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure and Co-Distilled with diethyl ether and dried invacuo to afford title compound 213 (200 mg, HCl salt) as a yellow solid.TLC: 5% MeOH/DCM (R_(f). 0.3). This was used in the next step withoutfurther characterization. Synthesis of5-ethyl-2-methoxy-N-(4-methoxy-6-(3-(4-propioloylpiperazin-1-yl) phenyl)benzo[d]isoxazol-3-yl) benzenesulfonamide

To a stirred solution of compound 213 (200 mg, 0.357 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.187 mL, 1.073 mmol), propiolic acid (50 mg,0.714 mmol) followed by T₃P as a 50% solution in EtOAc (0.340 mL, 0.535mmol). The reaction mixture was allowed to stir at room temperature for2 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and crude was purified by prep HPLCto afford the title compound (65 mg, 31.70%) as an off-white solid. TLC:5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 99

Synthesis of tert-butyl 1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate

To a stirred solution of compound 17 (300 mg, 0.778 mmol) in THF (5 mL)at 0° C. was added Na^(t)OPn (428 mg, 3.89 mmol) followed by5-ethyl-2-methoxybenzenesulfonyl chloride (365 mg, 1.556 mmol) and thereaction was allowed to stir at 60° C. for 2 h. After completion(monitored by TLC), the reaction mixture was quenched with water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude was purified by Combi flash column chromatography using agradient method of 20-60% EtOAc/Heptane to afford the title compound 214(200 mg, 44.15%, obtained as a mixture of regioisomers) as a pale-yellowsolid. TLC: 100% EtOAc (R_(f). 0.5). LCMS Calculated for: C28H33N5O7S:583.21; Found: 584.5 (M+1).

Synthesis of5-ethyl-2-methoxy-N-(4-methoxy-6-((5-(2,2,2-trifluoroacetyl)-5,6-dihydro-514-pyrrolo[3,4-c]pyrazol-1(4H)-yl) methyl) benzo[d]isoxazol-3-yl) benzenesulfonamide(215)

To a stirred solution of compound 214 (150 mg, 0.256 mmol) in DCM (2 mL)at 0° C. was added TFA (0.2 mL, 2.569 mmol). The reaction mixture wasallowed to stir at room temperature for 2 h. After completion (monitoredby TLC), reaction mixture was concentrated under reduced pressure,triturated with diethyl ether to afford the title crude compound 215(160 mg, TFA salt) as a gummy brown solid. TLC: 5% MeOH/DCM (R_(f).0.2). This mixture of regioisomers was used in the next step withoutfurther characterization.

Synthesis of5-ethyl-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 215 (150 mg, 0.258 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.135 mL, 0.775 mmol), propiolic acid (27 mg,0.387 mmol) followed by T₃P as a 50% solution in EtOAc (0.328 mL, 0.516mmol). The reaction mixture was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. The crude was purified by usingchiral HPLC purification to afford the title compound5-ethyl-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide(8.5 mg, 6.1%) as an off white solid. TLC: 5% MeOH/DCM (R_(f). 0.5) (SeeTable 1 for analytical data). The other regioisomer could not beisolated in sufficient quantity for analysis or testing.

Synthetic Example 100

Synthesis of tert-butyl 4-(3-bromophenyl)-1,4-diazepane-1-carboxylate(217)

To a stirred solution of compound 216 (1 g, 4.328 mmol) in toluene (15mL) was added Na^(t)OBu (1.22 g, 12.716 mmol) followed by tert-butyl1,4-diazepane-1-carboxylate (1.04 g, 5.193 mmol) and purged with argongas for 10 min followed by addition of XantPhos (500 mg, 0.865 mmol) andPd₂dba₃ (396 mg, 0.432 mmol). The reaction mixture was stirred at 120°C. for 16 h. After completion (monitored by TLC), the reaction mixturewas filtered through a pad of celite, and the filtrate was quenched withice cold water and extracted with ethyl acetate. The organic layer waswashed with brine solution dried over sodium sulphate and concentratedunder reduced pressure to get crude compound. The crude was purified bycombi flash chromatography using gradient 15% EA\Heptane to offer thetitle compound 217 (400 mg, 26.66%) as a colourless liquid. LCMSCalculated for C16H23BrN2O2: 354.09; Found: 355.3 (M+1).

Synthesis of tert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4-diazepane-1-carboxylate(218)

To a stirred solution of compound 217 (400 mg, 1.125 mmol) in 1,4Dioxane (3 mL) at room temperature was added B₂pin₂ (428 mg, 1.688mmol), KOAc (0.331 mg, 3.375 mmol). The reaction mixture was degassedfor 10 min followed by addition of Pd(dppf)Cl₂·DCM (92 mg, 0.1125 mmol).The reaction mixture was stirred at 100° C. for 16 h. After completion(monitored by TLC), the reaction mixture was quenched with ice coldwater, filtered through a Celite pad and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound 218(1.2 g, crude) as a brown semi-solid. TLC: 50% EtOAc/Heptane (R_(f).0.5). LCMS Calculated for C22H35BN2O4: 402.27; Found: 403.5 and 321.6(M+1). (Crude obtained as a mixture of corresponding boronic acid andboronate ester).

Synthesis of tert-butyl 4-(3-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)phenyl)-1,4-diazepane-1-carboxylate(219)

To a stirred solution of 116 (500 mg, 1.127 mmol) in 3:1 mixture of 1,4Dioxane:water (10 mL) was added K₂CO₃ (467 mg, 3.383 mmol), compound 218and purged with argon gas for 10 min followed by addition of Pd(dppf)Cl₂(92 mg, 0.112 mmol). The resulting reaction mixture was stirred at 80°C. for 16 h. After completion (monitored by TLC), the reaction mixturewas quenched with water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycombi flash chromatography (using a gradient method of 0-30%EtOAc/Heptane) to afford the title compound 219 (330 mg, 45.83%) as anoff-white solid. TLC: 40% EtOAc/Heptane (R_(f). 0.5). LCMS Calculatedfor C32H38N4O8S: 638.24; Found: 639.5 (M+1).

Synthesis of N-(6-(3-(1,4-diazepan-1-yl)phenyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamidehydrochloride (220)

To a stirred solution of compound 219 (300 mg, 0.521 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in 1,4 Dioxane (1.3 mL, 5.216 mmol). Thereaction was allowed to stir at the room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure and Co-Distilled with diethyl ether to affordtitle compound 220 (200 mg, HCl salt) as a yellow solid. TLC: 5%MeOH/DCM (Rf 0.3). This was used in the next step without furthercharacterization.

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(3-(4-propioloyl-1,4-diazepan-1-yl)phenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 220 (150 mg, 0.260 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.136 mL, 0.782 mmol), Propiolic acid (27 mg,0.39 mmol) followed by T₃P as a 50% solution in EtOAc (0.330 mL, 0.52mmol). The reaction mixture was allowed to stir at room temperature for1 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and crude was purified by using prepHPLC to afford the title compound (60 mg, 38.96%) as an off white solid.TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 101

Synthesis of tert-butyl 4-(3-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) phenyl)piperidine-1-carboxylate (221)

To a stirred solution of compound 204 (500 mg, 1.224 mmol) andtert-butyl 4-(3-bromophenyl) piperidine-1-carboxylate (386 mg, 1.469mmol) in a 2:1 mixture of 1,4 Dioxane: water (9 mL), was added K₂CO₃(507 mg, 3.672 mmol). The reaction mixture was degassed with Argonatmosphere followed by addition of Pd(dppf)Cl₂ (99 mg, 0.1224 mmol). Thereaction mixture was stirred at 80° C. for 16 h. After completion(monitored by TLC), the reaction mixture was diluted with ethyl-acetate,filtered on a Celite pad and the reaction mixture was concentrated underreduced pressure. The crude was purified by combi flash-chromatographyusing a gradient method of 0-30% EtOAc/Heptane to afford the compound221 (270 mg, 38.24%) as a pale-yellow solid. TLC: 40% EtOAc/Heptane(R_(f). 0.4). LCMS Calculated for C32H37N3O8S: 623.23; Found: 624.02(M+1).

Synthesis of 2,6-dimethoxy-N-(4-methoxy-6-(3-(piperidin-4-yl)phenyl)benzo[d]isoxazol-3-yl)benzenesulfonamide hydrochloride (222)

To a stirred solution of compound 221 (120 mg, 0.192 mmol) in DCM (4 mL)at 0° C. was added 4M HCl in dioxane (0.48 mL, 1.923 mmol). The reactionwas allowed to stir at the room temperature for 2 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure. The crude was triturated with diethyl ether and dried underreduced pressure to afford the title compound 222 (180 mg, HCl salt) asa colorless gummy solid. TLC: 5% MeOH/DCM (R_(f). 0.5). This was used inthe next step without further characterization.

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(3-(1-propioloylpiperidin-4-yl) phenyl)benzo[d]isoxazol-3-yl) benzenesulfonamide

To a stirred solution of compound 222 (180 mg, 0.321 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.168 mL, 0.963 mmol), Propiolic acid (26 mg,0.385 mmol) followed by T₃P as a 50% solution in EtOAc (0.612 mL, 0.963mmol). The reaction mixture was allowed to stir at room temperature for1 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (45 mg, 24.32%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 102

Synthesis of tert-butyl 4-(4-bromothiazol-2-yl) piperazine-1-carboxylate(224)

To a stirred solution of compound 223 (1.5 g, 9.145 mmol) in DMF (10 mL)at 0° C. was added K₂CO₃ (3.79 g, 27.435 mmol) followed by tert-butylpiperazine-1-carboxylate (2.0 g, 10.974 mmol). The reaction mixture wasallowed to stir at 100° C. for 16 h. After completion (monitored byTLC), the reaction mixture was quenched with ice cold water andextracted with EtOAc. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Thecrude was purified by combi flash chromatography using gradient 2-8%EA/Heptane to afford the title compound 224 (1.6 g, 74%) as an off-whitesolid. TLC:5% MeOH/DCM (R_(f). 0.5). LCMS Calculated for C12H19N3O2S:269.12; Found: 270.05 (M+H).

Synthesis of tert-butyl 4-(2-bromothiazol-5-yl) piperazine-1-carboxylate(225)

To a stirred solution of tert-butyl 4-(thiazol-5-yl)piperazine-1-carboxylate 224 (1.6 g, 5.940 mmol) in THF (60 mL) wasadded n-BuLi [1.6 mol/L in hexanes (5.56 mL, 8.910 mmol)] at −78° C. Thereaction mixture was stirred at −78° C. for 40 min, and a solution ofCBr₄ (2.95 g, 8.910 mmol) 1.5 mL in THF was added. The reaction mixturewas stirred at −78° C. for another 1 h. After completion (monitored byTLC), the reaction mixture was quenched with ice cold water andextracted with EtOAc. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Thecrude was purified by combi flash chromatography using gradient 4-8%EA/Heptane to afford the title compound 225 (1.6 g, 77.66%) as a brownsemi solid. TLC:5% MeOH/DCM (R_(f). 0.7). LCMS Calculated forC12H18BrN3O2S: 347.03; Found: 348.05 (M+H).

Synthesis of tert-butyl 4-(2-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) thiazol-5-yl)piperazine-1-carboxylate (226)

To a stirred solution of compound 225 (200 mg, 0.574 mmol) in 3:1mixture of 1,4 Dioxane: water (10 mL) was added K₂CO₃ (238 mg, 1.722mmol) and compound 204 (281 mg, 0.688 mmol). The reaction mixture waspurged with argon gas for 10 min and Pd (PPh₃)4 (33 mg, 0.0287 mmol) wasadded. The resulting reaction mixture was stirred at 100° C. for 16 h.After completion (monitored by TLC), the reaction mixture was quenchedwith ice cold water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by combi flashchromatography (using a gradient method of 80-90% EtOAc/Heptane) toafford the title compound 226 (55 mg, 15.19%) as a brown semi solid.TLC: 80% EtOAc/Heptane (R_(f). 0.4). LCMS Calculated for C28H33N5O8S2:631.18; Found: 632.2 (M+H).

Synthesis of 2,6-dimethoxy-N-(4-methoxy-6-(5-(piperazin-1-yl)thiazol-2-yl) benzo[d]isoxazol-3-yl) benzenesulfonamide hydrochloride(227)

To a stirred solution of compound 226 (55 mg, 0.087 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in dioxane (0.21 mL, 0.870 mmol). The reactionwas allowed to stir at the room temperature for 3 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure. The crude was triturated with EtOAc (20 mL), DCM (20 mL) anddried in vacuo to afford the title compound 227 (53 mg, HCl salt) as acolorless gummy solid. TLC: 5% MeOH/DCM (R_(f). 0.2). This was used inthe next step without further characterization.

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(5-(4-propioloylpiperazin-1-yl)thiazol-2-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 227 (50 mg, 0.088 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.076 mL, 0.44 mmol), Propiolic acid (7.4 mg,0.105 mmol) followed by T₃P as a 50% solution in EtOAc (0.111 mL, 0.176mmol). The reaction mixture was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by prepHPLC to afford the title compound (5.8 mg, 11.37%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 103

Synthesis of tert-butyl 4-(2-chloropyridin-4-yl)piperazine-1-carboxylate (228)

To a stirred solution of compound 71 (1 g, 5.196 mmol) in ACN (10 mL),was added Cs₂CO₃ (2.5 g, 7.794 mmol) followed by tert-butylpiperazine-1-carboxylate (1.16 g, 6.235 mmol). The reaction mixture wasstirred at 90° C. for 16 h. After completion (monitored by TLC), thereaction mixture was quenched with ice cold water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by combi flash chromatography (using a gradientmethod of 0-30% EtOAc/Heptane) to afford the title compound 228 (600 mg,38.96%) as an off-white solid. TLC: 60% EtOAc/Heptane (R_(f). 0.4). LCMSCalculated for C14H20ClN3O2: 297.12; Found: 298.05 (M+H).

Synthesis of tert-butyl 4-(2-(3-(methoxycarbonyl)-5-methylphenyl)pyridin-4-yl) piperazine-1-carboxylate (229)

To a stirred solution of compound 228 (600 mg, 2.014 mmol) in 3:1mixture of 1,4 Dioxane: water (40 mL), was added K₂CO₃ (517 mg, 3.73mmol) and methyl3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (667mg, 2.417 mmol). The reaction mixture was purged with argon gas for 10min followed by addition of and PdCl₂(dppf) (73 mg, 0.10 mmol). Thereaction mixture was stirred at 90° C. for 12 h. After completion(monitored by TLC), the reaction mixture was quenched with water andextracted with ethyl acetate. The organic layer washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by combi flash chromatography (using a gradientmethod of 30-40% EtOAc/Heptane) to afford the title compound 229 (400mg, 48.25%) as a pale brown solid. TLC: 40% EtOAc/Heptane (R_(f). 0.5).LCMS Calculated for C23H29N3O4: 411.22; Found: 412.2 (M+1)

Synthesis of tert-butyl 4-(2-(3-(hydrazinecarbonyl)-5-methylphenyl)pyridin-4-yl)piperazine-1-carboxylate (230)

To a stirred solution of compound 229 (400 mg 0.972 mmol) in EtOH (20mL) was added hydrazine mono hydrate (0.291 mL, 5.832 mmol). Thereaction was allowed to stir at 90° C. for 8 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure to obtain crude which was triturated with DCM/n-Heptane andconcentrated under reduced pressure to afford the title compound 230(310 mg, 77.50%) as a pale-yellow gummy solid. TLC: 5% MeOH/DCM (R_(f).0.3). LCMS Calculated for C22H29N5O3: 411.23; Found: 412.01 (M+1).

Synthesis of tert-butyl 4-(2-(3-(2-((2-fluorophenyl) sulfonyl)hydrazine-1-carbonyl)-5-methylphenyl)pyridin-4-yl)piperazine-1-carboxylate(231)

To a stirred solution of compound 230 (200 mg, 0.486 mmol) in THF (2 mL)and Pyridine (2 mL, 24.7 mmol) at 0° C. was added2-fluorobenzenesulfonyl chloride (114 mg, 0.5832 mmol) at 0° C. Theresulted reaction mixture was stirred for 4 h at RT. After completion(monitored by TLC and LCMS), the reaction mixture was quenched with icewater and extracted with EtOAc. The organic layer was washed with brine,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude compound was purified by combi flash chromatography (using agradient method of 30-40% EtOAc/Heptane) to afford the title compound231 (220 mg, 79.71%) as pale brown solid. TLC: 50% EtOAc/Heptane (R_(f).0.6). LCMS Calculated for C28H32FN5O5S: 569.21; Found: 570.2 (M+1)

Synthesis of 2-fluoro-N′-(3-methyl-5-(4-(piperazin-1-yl) pyridin-2-yl)benzoyl) benzenesulfonohydrazide hydrochloride (232)

To a stirred solution of compound 231 (200 mg, 0.351 mmol) in DCM (3 mL)at 0° C. was added 4M HCl in dioxane (0.877 mL, 3.510 mmol). Thereaction was allowed to stir at the room temperature for 1 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure, triturated with Et₂₀ (10 mL) and dried in vacuo

to afford the title compound 232 (80 mg, HCl salt) as a brown semisolid. TLC: 5% MeOH/DCM (R_(f). 0.2). This was used in the next stepwithout further characterization

Synthesis of 2-fluoro-N′-(3-methyl-5-(4-(4-propioloylpiperazin-1-yl)pyridin-2-yl) benzoyl) benzenesulfonohydrazide

To a stirred solution of compound 232 (80 mg, 0.158 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.082 mL, 0.474 mmol), Propiolic acid (13 mg,0.189 mmol) followed by T₃P as a 50% solution in EtOAc (0.150 mL, 0.237mmol). The reaction mixture was allowed to stir at room temperature for16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by prepHPLC to afford the title compound (6 mg, 7.3%) as an off-white solid.TLC: 5% MeOH/DCM (Rf 0.5). (See Table 1 for analytical data)

Synthetic Example 104

Synthesis of tert-butyl 4-(thiazol-5-yl)-1,4-diazepane-1-carboxylate(233)

To a stirred solution of compound 223 (1 g, 18.290 mmol) in DMF (5 mL)at 0° C. was added K₂CO₃ (7.58 g, 54.871 mmol) and tert-butyl1,4-diazepane-1-carboxylate (7.3 g, 36.58 mmol). The reaction mixturewas allowed to stir at 100° C. for 16 h. After completion (monitored byTLC), the reaction mixture was quenched with ice cold water andextracted with EtOAc. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Thecrude was purified by combi flash chromatography using gradient 10%EA/Heptane to afford the title compound 233 (700 mg, 41%) as anoff-white solid. TLC:5% MeOH/DCM (R_(f). 0.5). LCMS Calculated forC13H21N3O2S: 283.14; Found: 284.05 (M+H).

Synthesis of tert-butyl4-(2-bromothiazol-5-yl)-1,4-diazepane-1-carboxylate (234)

To a stirred solution of 233 (700 mg, 2.470 mmol) in THF (20 mL) wasadded n-BuLi (1.6 mol/L) in hexanes (2.31 mL, 3.705 mmol) at −78° C. Thereaction mixture was stirred at −78° C. for 40 min, and a solution ofCBr₄ (1.2 g, 3.705 mmol) in THF (1.5 mL) was added. The reaction mixturewas stirred at −78° C. for another 1 h. After completion (monitored byTLC), the reaction mixture was quenched with ice cold water andextracted with EtOAc. The organic layer was washed with brine, driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Thecrude was purified by combi flash chromatography using gradient 5%EA/Heptane to afford the title compound 234 (600 mg, 67.11%) as a brownoil. TLC:5% EA/Heptane (R_(f). 0.7). LCMS Calculated for C13H20BrN3O2S:361.05; Found: 362.05 (M+H).

Synthesis of tert-butyl4-(2-(3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)thiazol-5-yl)-1,4-diazepane-1-carboxylate(235)

To a stirred solution of compound 234 (250 mg, 0.690 mmol) in 3:1mixture of 1,4 Dioxane: water (10 mL) was added K₂CO₃ (286 mg, 2.070mmol) and 204 (308 mg, 0.759 mmol). The reaction mixture was purged withargon gas for 10 min followed by addition of PdCl₂(dppf) (56 mg, 0.0690mmol). The resulting mixture was stirred at 80° C. for 6 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice cold water and extracted with ethyl acetate. The organic layerwashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound triturated Et₂₀/Heptane and driedunder reduced pressure to afford the title compound 235 (300 mg, 67.56%)as a brown semi solid. TLC: 50% EtOAc/Heptane (R_(f). 0.4). LCMSCalculated for C30H37N₅O₇S2: 643.21; Found: 644.2 (M+H).

Synthesis ofN-(6-(5-(1,4-diazepan-1-yl)thiazol-2-yl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamidehydrochloride (236)

To a stirred solution of compound 235 (250 mg, 0.388 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in dioxane (0.97 mL, 3.883 mmol). The reactionwas allowed to stir at the room temperature for 2 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure. The crude compound triturated with Et₂₀/Heptane and driedunder reduced pressure to afford the title compound 236 (160 mg, HClsalt) as a colourless gummy solid. TLC: 5% MeOH/DCM (R_(f). 0.2). Thiswas used in the next step without further characterization. [1037]5-ethyl-2-methoxy-N-(4-methoxy-6-(5-(4-propioloyl-1,4-diazepan-1-yl)thiazol-2-yl) benzo[d]isoxazol-3-yl) benzenesulfonamide

To a stirred solution of compound 236 (150 mg, 0.258 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.135 mL, 0.775 mmol), Propiolic acid (27 mg,0.387 mmol) followed by T₃P 50% solution in EtOAc (0.328 mL, 0.516mmol). The reaction mixture was allowed to stir at room temperature for2 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (5 mg, 3.24%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 105A and 105B

Synthesis of tert-butyl1-(4-cyano-3-fluoro-5-methoxybenzyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate and tert-butyl2-(4-cyano-3-fluoro-5-methoxybenzyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(237)

To a stirred solution of compound 87 (2 g, 8.194 mmol) in THF (5 mL) at0° C. was added DIPEA (2.86 mL, 16.388 mmol) followed by tert-butyl1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.01 g,9.014 mmol). The reaction was allowed to stir at 70° C. for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice cold water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude was purified by using combi flashchromatography using gradient 5% EA/Heptane to afford the title compound237 (2.1 g, 67.74%) as a yellow oil compound. TLC: 5% EA/Heptane (Rf0.7). LCMS Calculated for C20H23FN4O3: 386.18; Found: 387.05 (M+H).

Synthesis of tert-butyl 1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate andtert-butyl2-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(238)

To a stirred solution of compound 237 (2 g, 5.175 mmol) in a 6:1 mixtureof DMF: H₂O (7 mL) at room temperature was added N-hydroxyacetamide(1.165 g, 15.525 mmol) followed by K₂CO₃ (4.29 g, 31.053 mmol). Thereaction mixture was allowed to stir at 60° C. for 12 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice water and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to offer the title compound 238 (1.9 g, 76.92%, mixture ofregioisomers) as a brown semi-solid. TLC: 50% EtOAc/Heptane (R_(f).0.45). LCMS Calculated for C20H25N5O4: 399.19; Found: 400.02 (M+1).

Synthesis of tert-butyl 1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate andtert-butyl2-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(239)

To a stirred solution of compound 238 (300 mg, 0.751 mmol) in THF (10mL) was added NaO^(t)Pn (0.248 g, 2.253 mmol) followed by5-ethyl-2-methoxybenzenesulfonyl chloride (0.229 g, 0.976 mmol). Thereaction mixture was allowed to stir at the room temperature for 16 h.After completion (monitored by TLC), the reaction mixture was quenchedwith ice cold water and extracted with ethyl acetate. The organic layerwas dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The crude compound was purified by combi flash chromatography(neutral alumina) to afford the title compound 239 (200 mg, 44.64%,mixture of regioisomers) as a pale-yellow solid. TLC: 80 EtOAc (R_(f).0.5). LCMS Calculated for C29H35N5O7S:597.23; Found:598.5 (M+1).

Synthesis of5-ethyl-2-methoxy-N-(4-methoxy-6-((4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl) methyl)benzo[d]isoxazol-3-yl)benzenesulfonamidehydrochloride and5-ethyl-2-methoxy-N-(4-methoxy-6-((4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamidehydrochloride (240)

To a stirred solution of compound 239 (150 mg, 0.250 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in dioxane (0.627 mL, 2.509 mmol). Thereaction was allowed to stir at the room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentrated,triturated with Et₂₀ and dried under reduced pressure to afford thetitle compound 240 (160 mg, HCl salt, mixture of regioisomers) as acolourless gummy solid. TLC: 5% MeOH/DCM (R_(f). 0.2). This was used inthe next step without further characterization.

Synthesis of5-ethyl-2-methoxy-N-(4-methoxy-6-((5-propioloyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamideand5-ethyl-2-methoxy-N-(4-methoxy-6-((5-propioloyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 240 (150 mg, 0.280 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.073 mL, 0.421 mmol), Propiolic acid (58 mg,0.84 mmol) followed by T₃P 50% solution in EtOAc (0.356 mL, 0.56 mmol)and the mixture was allowed to stir at room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentrated andthe crude was purified by chiral HPLC to afford the5-ethyl-2-methoxy-N-(4-methoxy-6-(5-(4-propioloyl-1,4-diazepan-1-yl)thiazol-2-yl) benzo[d]isoxazol-3-yl) benzenesulfonamide (8.5 mg, 5.5%)as an off-white solid and5-ethyl-2-methoxy-N-(4-methoxy-6-((5-propioloyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl) methyl) benzo[d]isoxazol-3-yl) benzenesulfonamide (2 mg,1.29%) as an off-white solid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table1 for analytical data).

Synthetic Example 106

Synthesis of tert-butyl 4-(thiazol-5-yl)piperazine-1-carboxylate (242)

To a stirred solution of compound 241 (2 g, 8.233 mmol) in DMF (10 mL)at 0° C. was added K₂CO₃ (3.41 g, 24.699 mmol), followed by tert-butylpiperazine-1-carboxylate (2.3 g, 12.349 mmol). The reaction mixture wasallowed to stir at 70° C. for 16 h. After completion (monitored by TLC),the reaction mixture was quenched with ice cold water and extracted withEtOAc. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, and concentrated under reduced pressure. The crude was purifiedby combi flash chromatography using gradient 2-5% EA/Heptane to affordthe title compound 242 (1.4 g, 56.45%) as an off-white solid. TLC:5%MeOH/DCM (R_(f). 0.6). LCMS Calculated for C12H18BrN3O2S: 347.03; Found:348.05 (M+H).

Synthesis of tert-butyl4-(5-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)thiazol-2-yl)piperazine-1-carboxylate(243)

To a stirred solution of compound 242 (600 mg, 1.722 mmol) in 3:1mixture of 1,4 Dioxane: water (10 mL) was added K₂CO₃ (714 mg, 5.168mmol) followed by compound 204 (843 mg, 2.066 mmol). The reactionmixture was purged with argon gas for 10 min followed by addition ofPdCl₂dppf.DCM (140 mg, 0.1722 mmol). The reaction mixture was stirred at80° C. for 8 h. After completion (monitored by TLC), the reactionmixture was quenched with ice cold water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by combi flash chromatography (using a gradient method of80-90% EtOAc/Heptane) to afford the title compound 243 (200 mg, 18.51%)as a pale-yellow solid. TLC: 80% EtOAc/Heptane (R_(f). 0.4). LCMSCalculated for C28H33N5O8S2: 631.18; Found: 632.2 (M+H).

Synthesis of 2,6-dimethoxy-N-(4-methoxy-6-(2-(piperazin-1-yl)thiazol-5-yl) benzo[d]isoxazol-3-yl) benzenesulfonamide hydrochloride(244)

To a stirred solution of compound 243 (200 mg, 0.316 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in dioxane (0.79 mL, 3.165 mmol). The reactionwas allowed to stir at the room temperature for 16 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure and triturated with EtOAc/Heptane to afford the title compound244 (150 mg, HCl salt) as a colourless gummy solid. TLC: 5% MeOH/DCM(R_(f). 0.2). LCMS Calculated for C23H26ClN5O6S2: 567.10; Found: 568.2

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(2-(4-propioloylpiperazin-1-yl)thiazol-5-yl) benzo[d]isoxazol-3-yl) benzenesulfonamide

To a stirred solution of compound 244 (150 mg, 0.264 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.138 mL, 0.792 mmol), Propiolic acid (36 mg,0.528 mmol) followed by T₃P as a 50% solution in EtOAc (0.335 mL, 0.528mmol). The reaction mixture was allowed to stir at room temperature for1 h. After completion (monitored by TLC), the reaction mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure. The crude was purified by using combi flashchromatography using gradient 20-50% EA/Heptane to afford the titlecompound (98 mg, 63.63%) as an off-white solid. TLC: 5% MeOH/DCM (R_(f).0.4). (See Table 1 for analytical data).

Synthetic Example 107

To a stirred solution of compound 178 (150 mg, 0.317 mmol) in DCM (2 mL)at 0° C. was added TEA (0.133 mL, 0.953 mmol) and followed by ethenesulfonyl chloride (48 mg, 0.381 mmol) in DCM (1 mL). The reaction wasallowed to stir at 0° C. for 1 h. After completion (monitored by TLC),the reaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, concentrated and purified by prep HPLC to afford the titlecompound (6 mg, 3.4%) as a yellow solid. TLC: 5% MeOH/DCM (R_(f). 0.40).(See Table 1 for analytical data).

Synthetic Example 108

To a stirred solution of compound 58 (120 mg, 0.235 mmol) in DCM (2 mL)at 0° C. was added TEA (0.1 mL, 0.705 mmol) and followed byethanesulfonyl chloride (33 mg, 0.258 mmol) in DCM (0.5 mL). Thereaction was allowed to stir at 0° C. for 1 h. After completion(monitored by TLC), the reaction mixture was quenched with ice coldwater and extracted with DCM. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, concentrated and purified by prep HPLC toafford the title compound (40 mg, 27.63%) as an off-white solid. TLC: 5%MeOH/DCM (Rf: 0.40). (See Table 1 for analytical data).

Synthetic Example 109

Synthesis of tert-butyl (S)-3-((4-cyano-3-fluoro-5-methoxybenzyl) oxy)pyrrolidine-1-carboxylate (245)

To a stirred solution of compound 87 (500 mg, 2.048 mmol) inacetonitrile (5 mL) at 0° C. was added K₂CO₃ (0.849 mg, 6.146 mmol)followed by tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (557 mg,3.072 mmol). The reaction was allowed to stir at 60° C. for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice cold water and extracted with Ethyl Acetate. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated underreduced pressure to get the title compound 245 (500 mg, 48.81%) ascolour less gummy solid. TLC: 50% EtOAc (R_(f). 0.5). LCMS Calculatedfor C18H23FN2O4: 350.16; Found: 351.02 (M+1). The crude compound wasused in next reaction without purification.

Synthesis of tert-butyl (S)-3-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methoxy) pyrrolidine-1-carboxylate (246)

To a stirred solution of compound 245 (500 mg, 1.426 mmol) in a 7:1mixture of DMF: H₂O (8 mL) at room temperature was addedN-hydroxyacetamide (0.214 g, 2.853 mmol) followed by K₂CO₃ (591 mg,4.278 mmol). The reaction mixture was allowed to stir at 60° C. for 16h. After completion (monitored by TLC), the reaction mixture wasquenched with ice water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous Na₂SO₄, concentratedand purified by combi flash chromatography using gradient 40-70%EA/Heptane to afford the title compound 246 (210 mg, 76.92%) as a yellowsolid. TLC: 70% EtOAc/Heptane (R_(f). 0.40). LCMS Calculated forC18H25N3O5: 363.18; Found: 364.02 (M+1).

Synthesis of tert-butyl (S)-3-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) methoxy)pyrrolidine-1-carboxylate (247)

To a stirred solution of compound 246 (210 mg, 0.577 mmol) in THF (10mL) was added NatOPn (0.190 g, 1.733 mmol) followed by5-ethyl-2-methoxybenzenesulfonyl chloride (0.162 g, 0.692 mmol). Thereaction mixture was allowed to stir at the room temperature for 5 h.After completion (monitored by TLC), the reaction mixture was quenchedwith ice water and extracted with ethyl acetate. The organic layer wasdried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The crude compound was purified by combi flash chromatography (neutralalumina) to afford the title compound 247 (150 mg, 46.29%) as apale-yellow solid. TLC: 50 EtOAc (R_(f). 0.5). LCMS Calculated forC27H35N3O8S:561.21; Found:562.5 (M+1).

Synthesis of (S)-5-ethyl-2-methoxy-N-(4-methoxy-6-((pyrrolidin-3-yloxy)methyl) benzo[d]isoxazol-3-yl) benzenesulfonamide hydrochloride (248)

To a stirred solution of compound 247 (150 mg, 0.267 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in dioxane (0.66 mL, 2.670 mmol). The reactionwas allowed to stir at the room temperature for 2 h. After completion(monitored by TLC), the reaction mixture quenched with ice cold waterand extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, concentrated triturated with EtOAc/Heptane to afford the titlecompound 248 (120 mg, HCl salt) as a colour less sticky solid. TLC: 5%MeOH/DCM (R_(f). 0.2). LCMS Calculated for C22H27N3O6S: 461.16; Found:462.10

Synthesis of(S)-5-ethyl-2-methoxy-N-(4-methoxy-6-(((1-propioloylpyrrolidin-3-yl)oxy) methyl) benzo[d]isoxazol-3-yl) benzenesulfonamide

To a stirred solution of compound 248 (120 mg, 0.240 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.125 mL, 0.72 mmol), Propiolic acid (20 mg,0.289 mmol) followed by T₃P as a 50% solution in EtOAc (0.229 mL, 0.36mmol). The reaction mixture was allowed to stir at room temperature for1 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (50 mg, 40.65%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 110

Synthesis of tert-butyl(R)-3-((4-cyano-3-fluoro-5-methoxybenzyl)oxy)pyrrolidine-1-carboxylate(249)

To a stirred solution of compound 87 (250 mg, 1.024 mmol) in ACN (5 mL)at 0° C. was added K₂CO₃ (0.424 mg, 3.073 mmol) followed by tert-butyl(R)-3-hydroxypyrrolidine-1-carboxylate (557 mg, 1.536 mmol). Thereaction was allowed to stir at 60° C. for 16 h. After completion(monitored by TLC), the reaction mixture was quenched with water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, concentrated to afford the title compound249 (300 mg, 83.79%) as off-white solid. TLC: 50% EtOAc (R_(f). 0.5).LCMS Calculated for C18H23FN2O4: 350.16; Found: 351.02 (M+1). The crudecompound used in next reaction without purification.

Synthesis of tert-butyl (R)-3-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methoxy) pyrrolidine-1-carboxylate (250)

To a stirred solution of compound 249 (300 mg, 0.856 mmol) in a 6:1mixture of DMF: H₂O (7 mL) at room temperature was added N-hydroxyacetamide (0.128 g, 1.712 mmol) followed by K₂CO₃ (355 mg, 2.568 mmol).The reaction mixture was allowed to stir at 60° C. for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice water added and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄, concentrated underreduced pressure and purified by combi flash chromatography usinggradient 40-70% EA/Heptane to afford the compound 250 (150 mg, 48.23%)as a pale-yellow solid. TLC: 80% EtOAc/Heptane (R_(f). 0.40). LCMSCalculated for C18H25N3O5: 363.18; Found: 364.5 (M+1).

Synthesis of tert-butyl (R)-3-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methoxy)pyrrolidine-1-carboxylate(251)

To a stirred solution of compound 250 (150 mg, 0.412 mmol) in THF (10mL) was added NaO^(t)Bu (0.135 g, 1.236 mmol) followed by5-ethyl-2-methoxybenzenesulfonyl chloride (0.116 g, 0.495 mmol). Thereaction mixture was allowed to stir at 70° C. for 12 h. Aftercompletion (reaction monitored by TLC), the reaction mixture wasquenched with ice water and extracted with ethyl acetate. The organiclayer was dried over anhydrous Na₂SO₄, and concentrated under reducedpressure. The crude compound was purified by combi flash chromatography(neutral alumina) to afford the title compound 251 (100 mg, 43.29%), asa yellow solid. TLC: 60% EtOAc/Heptane (R_(f). 0.4). LCMS Calculated forC27H35N3O8S:561.21; Found:562.5 (M+1).

Synthesis of (R)-5-ethyl-2-methoxy-N-(4-methoxy-6-((pyrrolidin-3-yloxy)methyl) benzo[d]isoxazol-3-yl) benzenesulfonamide hydrochloride (252)

To a stirred solution of compound 251 (100 mg, 0.276 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in dioxane (0.69 mL, 2.76 mmol). The reactionwas allowed to stir at the room temperature for 4 h. After completion(monitored by TLC), the reaction mixture was concentrated trituratedwith EtOAc/Heptane to afford the title compound 252 (90 mg, HCl salt) asan off-white semi solid. TLC: 5% MeOH/DCM (R_(f). 0.2). LCMS Calculatedfor C22H27N3O6S: 461.16; Found: 462.1

Synthesis of(R)-5-ethyl-2-methoxy-N-(4-methoxy-6-(((1-propioloylpyrrolidin-3-yl)oxy) methyl) benzo[d]isoxazol-3-yl) benzenesulfonamide

To a stirred solution of compound 252 (90 mg, 0.180 mmol) in DMF (1 mL)at 0° C. was added DIPEA (0.094 mL, 0.542 mmol), Propiolic acid (15 mg,0.216 mmol) followed by T₃P as a 50% solution in EtOAc (0.229 mL, 0.36mmol). The reaction mixture was allowed to stir at room temperature for1 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (17 mg, 18.37%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 111

Synthesis of tert-butyl 4-(3-(3-amino-4-methoxybenzo[d]isoxazol-6-yl)phenyl) piperazine-1-carboxylate (253)

To a stirred solution tert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(798 mg, 2.057 mmol) in dry 1,4-Dioxane (10 mL) was added compound 116(500 mg, 2.057 mmol) and K₂CO₃ (710 mg, 5.142 mmol). The reaction waspurged with argon gas for 5 min followed by addition of Pd(dppf)Cl₂ (134mg, 0.164 mmol). The reaction mixture was stirred at 80° C. for 4 h.After completion (monitored by TLC), the reaction mixture was filteredthrough a pad of celite, the filtrate was concentrated to get crude. Thecrude was purified by combi flash using gradient 36-50% EA/PE to affordthe title compound 253 (400 mg, 45.81%) as a white solid. TLC: 50%EtOAc/Heptane (Rf 0.4). LCMS Calculated for C23H28N4O4: 424.21; Found:425.02 (M+1).

Synthesis of tert-butyl 4-(3-(3-((N-cyclohexylsulfamoyl)amino)-4-methoxybenzo[d]isoxazol-6-yl) phenyl) piperazine-1-carboxylate(254)

To a stirred solution of compound 253 (200 mg, 0.471 mmol) in THF (10mL) was added Na^(t)OPn (130 mg, 0.943 mmol) followed bycyclohexylsulfamoyl chloride (186 mg, 0.942 mmol). The reaction mixturewas allowed to stir at the room temperature for 16 h. After completion(monitored by TLC), the reaction mixture was quenched with ice water andextracted with ethyl acetate. The organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by combi flash chromatography (neutral alumina) to afford thetitle compound 254 (150 mg, 54.54%), as a light-yellow solid. TLC: 80EtOAc (R_(f). 0.5). LCMS Calculated for C29H39N5O6S: 585.26; Found:586.5(M+1).

Synthesis of 4-(3-(3-((N-cyclohexylsulfamoyl)amino)-4-methoxybenzo[d]isoxazol-6-yl) phenyl) piperazine Hydrochloride(255)

To a stirred solution of compound 254 (150 mg, 0.256 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in dioxane (0.64 mL, 2.560 mmol). The reactionwas allowed to stir at the room temperature for 2 h. After completion(reaction monitored by TLC), the reaction mixture was concentrated underreduced pressure and triturated with ether to afford the title compound255 (120 mg, crude HCl salt,) as pale-yellow solid. TLC: 5% MeOH/DCM (Rf0.3). LCMS Calculated for C24H31N5O4S: 485.21: Found: 486.4.

Synthesis of N-[(1S)-1-[[4-(6-methoxy-4-methyl-3-pyridyl) phenyl]methyl]-2-(methylamino)-2-oxo-ethyl] thiazolo [4,5-c]pyridine-6-carboxamide

To a stirred solution of compound 255 (120 mg, 0.229 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.12 mL, 0.687 mmol), propiolic acid (32 mg,0.458 mmol) followed by T₃P as a 50% solution in EtOAc (0.437 mL, 0.687mmol). The reaction mixture was allowed to stir at room temperature for1 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (20 mg, 16.26%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 112

Synthesis of tert-butyl 4-(3-(3-((N-cyclohexyl-N-methylsulfamoyl)amino)-4-methoxybenzo[d]isoxazol-6-yl) phenyl) piperazine-1-carboxylate(256)

To a stirred solution of 253 (200 mg, 4.711 mmol) in THF (5 mL) wasadded KO^(t)Bu (105 mg, 0.942 mmol) followed bycyclohexyl(methyl)sulfamoyl chloride (199 mg, 9.422 mmol). The reactionmixture was allowed to stir at the room temperature for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice water and extracted with ethyl acetate. The organic layer was driedover anhydrous Na₂SO₄, and concentrated under reduced pressure. Thecrude compound was purified by combi flash chromatography using (neutralalumina) gradient 30-50% EA/Heptane to afford the title compound 256(150 mg, 54.54%) as a light-yellow solid. TLC: 80 EtOAc (R_(f). 0.6).LCMS Calculated for C30H41N5O6S: 599.28; Found: 600.5 (M+1).

Synthesis of 3-[[cyclohexyl(methyl)sulfamoyl]amino]-4-methoxy-6-(3-piperazin-1-ylphenyl)-1,2-benzoxazole;hydrochloride (257)

To a stirred solution of compound 256 (120 mg, 0.223 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in dioxane (0.559 mL, 2.238 mmol). Thereaction was allowed to stir at the room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedtriturated with ether to afford the title compound 257 (140 mg, crudeHCl salt,) as pale-yellow solid. TLC: 5% MeOH/DCM (R_(f). 0.3). LCMSCalculated for C25H33N5O4S: 499.23: Found: 500.3.

Synthesis of 3-[[cyclohexyl(methyl)sulfamoyl]amino]-4-methoxy-6-[3-(4-prop-2-ynoylpiperazin-1-yl)phenyl]-1,2-benzoxazole

To a stirred solution of compound 257 (120 mg, 0.223 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.117 mL, 0.671 mmol), propiolic acid (31 mg,0.44 mmol) followed by T₃P as a 50% solution in EtOAc (0.425 mL, 0.669mmol). The reaction mixture was allowed to stir at room temperature for1 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (28 mg, 22.76%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 113

Synthesis of 6-chloro-4-methoxyisoxazolo[5,4-b]pyridin-3-amine (259)

To a stirred solution of compound 258 (8 g, 39.41 mmol; synthesized asreported in WO 2018/106459 A1) in a 7:1 mixture of CH₃CN (100 mL) atroom temperature was added N-hydroxyacetamide (2.96 g, 39.41 mmol)followed by K₂CO₃ (5.44 g, 39.41 mmol). The reaction mixture was allowedto stir at RT for 3 h. After completion (monitored by TLC), the mixturewas quenched with ice water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,concentrated and purified by combi flash chromatography using gradient20-60% EA/Heptane to afford the title compound 259 (1.4 g, 17.80%) as anoff-white solid. TLC: 70% EtOAc/Heptane (Rf: 0.40). LCMS Calculated forC7H6ClN3O2: 199.01; Found: 200.10 (M+1).

Synthesis ofN-(6-chloro-4-methoxyisoxazolo[5,4-b]pyridin-3-yl)-2,6-dimethoxybenzenesulfonamide(260)

To a stirred solution of compound 259 (1.4 g, 7.01 mmol) in THF (30 mL)was added KO^(t)Bu 1M solution in THF (14 mL, 14.02 mmol) followed by2,6-dimethoxybenzenesulfonyl chloride (2.98 g, 12.62 mmol). The reactionmixture was allowed to stir at the room temperature for 5 h. Aftercompletion (monitored by TLC), the mixture was quenched with ice waterand extracted with ethyl acetate. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by combi flash chromatography (neutral alumina) toafford the title compound 260 (600 mg, 20.76%) as a pale-yellow solid.TLC: 50 EtOAc (R_(f). 0.5). LCMS Calculated for C15H14ClN3O6S: 399.03;Found: 399.80 (M+1).

Synthesis of tert-butyl4-(3-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxyisoxazolo[5,4-b]pyridin-6-yl)phenyl)piperazine-1-carboxylate(261)

To a stirred solution tert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(350 mg, 0.90 mmol) in dry 1,4-Dioxane (10 mL) was added compound 260(300 mg, 0.75 mmol) and K₂CO₃ (311 mg, 2.25 mmol). The reaction waspurged with argon gas for 5 min followed by addition of Pd(dppf)Cl₂(54.9 mg, 0.075 mmol). The reaction mixture was stirred at 80° C. for 2h. After completion (monitored by TLC), the reaction mixture wasfiltered through a pad of celite, the filtrate was concentrated to getcrude. The crude product was used as such in the next reaction withoutpurification.

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(3-(piperazin-1-yl)phenyl)isoxazolo[5,4-b]pyridin-3-yl)benzenesulfonamidehydrochloride (262)

To a stirred solution of compound 261 (500 mg, 0.80 mmol) in DCM (4 mL)at 0° C. was added 4M HCl in dioxane (0.8 mL, 3.20 mmol). The reactionwas allowed to stir at the room temperature for 2 h. After completion(monitored by TLC), the reaction mixture quenched with ice cold waterand extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, concentrated triturated with Et₂₀ to afford the title compound262 (200 mg, HCl salt) as a light brown solid. TLC: 5% MeOH/DCM (R_(f).0.2). LCMS Calculated for C25H27N5O6S: 525.17; Found: 526.10.

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(3-(4-propioloylpiperazin-1-yl)phenyl)isoxazolo[5,4-b]pyridin-3-yl)benzenesulfonamide

To a stirred solution of compound 262 (200 mg, 0.35 mmol) in DMF (3 mL)at 0° C. was added DIPEA (0.25 mL, 1.42 mmol), Propiolic acid (30 mg,0.43 mmol) followed by T₃P as a 50% solution in EtOAc (0.453 mL, 0.71mmol). The reaction mixture was allowed to stir at room temperature for1 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (9.0 mg, 5.00%) as a light brownsolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 114

Synthesis ofN-(6-chloro-4-methoxyisoxazolo[5,4-b]pyridin-3-yl)-5-ethyl-2-methoxybenzenesulfonamide(263)

To a stirred solution of compound 259 (300 mg, 7.01 mmol) in THF (30 mL)was added NaH as a 60% dispersion in oil (14 mL, 14.02 mmol) followed by5-ethyl-2-methoxybenzenesulfonyl chloride (2.98 g, 12.62 mmol). Thereaction mixture was allowed to stir at the room temperature for 5 h.After completion (monitored by TLC), the reaction mixture was quenchedwith ice cold water and extracted with ethyl acetate. The organic layerwas dried over anhydrous Na₂SO₄ and concentrated under reduced pressure.The crude compound was purified by combi flash chromatography (neutralalumina) to afford the title compound 263 (350 mg, 20.76%) as apale-yellow solid. TLC: 50 EtOAc (R_(f). 0.5). LCMS Calculated forC16H16ClN3O5S: 397.05; Found: 398.10 (M+1).

Synthesis of tert-butyl4-(3-(3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxyisoxazolo[5,4-b]pyridin-6-yl)phenyl)piperazine-1-carboxylate(264)

To a stirred solution tert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(350 mg, 0.90 mmol) in dry 1,4-Dioxane (10 mL) was added compound 263(300 mg, 0.75 mmol) and K₂CO₃ (311 mg, 2.25 mmol). The mixture waspurged with argon gas for 5 min followed by addition of Pd(dppf)Cl₂(54.9 mg, 0.075 mmol). The reaction mixture was stirred at 80° C. for 2h. After completion (monitored by TLC), the reaction mixture wasfiltered through a pad of celite, the filtrate was concentrated to getcrude. The crude product was purified by combi flash using gradient 60%EA/Heptane to afford the title compound 264 (80 mg, 14.62%) as a lightbrown solid. LCMS Calculated for C30H35N5O8S: 623.24; Found: 624.28(M+1).

Synthesis of5-ethyl-2-methoxy-N-(4-methoxy-6-(3-(piperazin-1-yl)phenyl)isoxazolo[5,4-b]pyridin-3-yl)benzenesulfonamidehydrochloride (265)

To a stirred solution of compound 264 (80 mg, 0.14 mmol) in DCM (4 mL)at 0° C. was added 4M HCl in dioxane (0.15 mL, 0.57 mmol). The reactionwas allowed to stir at the room temperature for 2 h. After completion(monitored by TLC), the reaction mixture quenched with ice cold waterand extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, concentrated triturated with Et₂₀ to afford the title compound265 (60 mg, HCl salt) as a light brown solid. TLC: 5% MeOH/DCM (R_(f).0.2). LCMS Calculated for C26H29N5O5S: 523.19; Found: 524.35.

Synthesis of25-ethyl-2-methoxy-N-(4-methoxy-6-(3-(4-propioloylpiperazin-1-yl)phenyl)isoxazolo[5,4-b]pyridin-3-yl)benzenesulfonamide

To a stirred solution of compound 265 (60 mg, 0.107 mmol) in DMF (3 mL)at 0° C. was added DIPEA (0.075 mL, 0.42 mmol), Propiolic acid (9.6 mg,0.128 mmol) followed by T₃P as a 50% solution in EtOAc (0.14 mL, 0.214mmol). The reaction mixture was allowed to stir at room temperature for1 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (6.0 mg, 10.3%) as a light brownsolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 115

Synthesis ofN-(6-(3-bromo-5-hydroxyphenyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide(267)

To a stirred solution compound 204 (600 mg, 1.47 mmol) in 3:1 mixture of1,4-Dioxane:H₂O (10 mL) was added compound 266 (667 mg, 2.64 mmol) andK₂CO₃ (610 mg, 4.41 mmol). The reaction was purged with argon gas for 5min followed by addition of Pd(dppf)Cl₂ (81 mg, 0.110 mmol). Thereaction mixture was stirred at 80° C. for 2 h. After completion(monitored by TLC), the reaction mixture was filtered through a pad ofcelite, the filtrate was concentrated to get crude. The crude productwas purified by combi flash using gradient 60% EA/Heptane to afford thetitle compound 267 (200 mg, 14.62%) as a light brown solid. LCMSCalculated for C22H19BrN2O7S: 534.01; Found: 535.20 (M+1).

Synthesis of tert-butyl4-(3-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)-5-hydroxyphenyl)piperazine-1-carboxylate(268)

To a stirred solution compound 267 (200 mg, 0.37 mmol) in dry DMF (3 mL)was added tert-butyl piperazine-1-carboxylate (83 mg, 0.44 mmol) andCs₂CO₃ (365 mg, 1.12 mmol). The reaction was purged with argon gas for 5min followed by addition of XPhosPdG3 (32 mg, 0.037 mmol). The reactionmixture was stirred at 80° C. for 16 h. After completion (monitored byTLC), the reaction mixture was filtered through a pad of celite, thefiltrate was concentrated to get crude. The crude product was purifiedby combi flash using gradient 60% EA/Heptane to afford the titlecompound 268 (150 mg, 62.76%) as a light brown solid. LCMS Calculatedfor C31H36N4O9S: 640.22; Found: 641.20 (M+1).

N-(6-(3-hydroxy-5-(piperazin-1-yl)phenyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamidehydrochloride (269)

To a stirred solution of compound 268 (150 mg, 0.234 mmol) in DCM (4 mL)at 0° C. was added 4M HCl in dioxane (0.6 mL, 2.34 mmol). The reactionwas allowed to stir at the room temperature for 2 h. After completion(monitored by TLC), the reaction mixture quenched with ice cold waterand extracted with ethyl acetate. The organic layer was dried overNa₂SO₄, concentrated triturated with Et₂₀ to afford the title compound269 (90 mg, HCl salt) as a light brown solid. TLC: 5% MeOH/DCM (R_(f).0.2). LCMS Calculated for C26H28N4O7S: 540.17; Found: 541.30.

Synthesis ofN-(6-(3-hydroxy-5-(4-propioloylpiperazin-1-yl)phenyl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide

To a stirred solution of compound 269 (90 mg, 0.16 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.11 mL, 0.62 mmol), propiolic acid (14 mg,0.198 mmol) followed by T₃P as a 50% solution in EtOAc (0.198 mL, 0.312mmol). The reaction mixture was allowed to stir at room temperature for1 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and the crude was purified by usingprep HPLC to afford the title compound (3.0 mg, 3.20%) as an off-whitesolid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data).

Synthetic Example 116

To a stirred solution of compound 151 (0.15 g, 0.296 mmol) in DMF (2 mL)at 0° C. was added TEA (0.17 mL, 1.183 mmol) followed by methanesulfonyl chloride (45 mg, 0.355 mmol). The reaction was allowed to stirat room temperature for 2 h. After completion (monitored by TLC), thereaction mixture was concentrated under reduced pressure to get browngummy crude. The crude was purified by combi-flash chromatography usinggradient of 5%-10% MeOH in DCM to get the desired compound which wasfurther purified by prep HPLC to afford the title compound (23 mg,14.19%) as an off-white solid. TLC: 10% MeOH/DCM (Rf: 0.40). (See Table1 for analytical data).

Synthetic Example 117

To a stirred solution of compound 253 (200 mg, 0.471 mmol) in THF (10mL) was added NaO^(t)Pn (0.103 g, 0.942 mmol) followed bycyclohexylmethanesulfonyl chloride (0.138 g, 0.706 mmol). The reactionmixture was allowed to stir at the room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice cold water and extracted with ethyl acetate. The organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude compound was purified by combi flash chromatography (neutralalumina) to afford the title compound 270 (60 mg, 21.810%) as apale-yellow solid. TLC: 50 EtOAc (R_(f). 0.5). LCMS Calculated forC30H40N4O6S:584.27; Found:585.5 (M+1).

Synthesis of1-cyclohexyl-N-(4-methoxy-6-(3-(piperazin-1-yl)phenyl)benzo[d]isoxazol-3-yl)methanesulfonamidehydrochloride (271)

To a stirred solution of compound 270 (60 mg, 0.102 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in 1,4 Dioxane (0.25 mL, 1.026 mmol). Thereaction was allowed to stir at the room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure and triturated with Et₂₀ and dried in vacuo toafford title compound 271 (50 mg, HCl salt) as a colourless stickysolid. TLC: 5% MeOH/DCM (R_(f). 0.3). LCMS calculated for C25H32N4O4S:484.21: Found: 485.30.

Synthesis of 1-cyclohexyl-N-(4-methoxy-6-(3-(4-propioloylpiperazin-1-yl)phenyl) benzo[d]isoxazol-3-yl) methanesulfonamide

To a stirred solution of compound 271 (50 mg, 0.095 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.05 mL, 0.287 mmol), propiolic acid (8 mg,0.114 mmol) followed by T₃P as a 50% solution in EtOAc (0.45 mg, 0.1425mmol). The reaction mixture was allowed to stir at room temperature for2 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and crude was purified by using prepHPLC to afford the title compound (4.5 mg, 8.33%) as an off-white solid.TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 for analytical data)

Synthetic Example 118

Synthesis ofN-(6-(4-bromothiazol-2-yl)-4-methoxybenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide(272)

To a stirred solution of compound 204 (1 g, 2.449 mmol) in 3:1 mixtureof 1,4 Dioxane: water (10 mL) was added K₂CO₃ (1.01g, 7.349 mmol)followed by 2,4-dibromothiazole (713 mg, 2.938 mmol). The reactionmixture was purged with argon gas for 10 min followed by addition ofPd(PPh₃)4 (0.282 g, 0.2449 mmol). The reaction mixture was stirred at80° C. for 4 h. After completion (monitored by TLC), the reactionmixture was quenched with ice cold water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The crude compound waspurified by combi flash chromatography (using a gradient method of 5-20%EtOAc/Heptane) to afford the title compound 272 (600 mg, 46.87%) as palebrown solid. TLC: 50% EtOAc/Heptane (R_(f). 0.6). LCMS Calculated forC19H16BrN3O6S2: 524.97; Found: 525.5 (M+H).

Synthesis of tert-butyl4-(2-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)thiazol-4-yl)piperazine-1-carboxylate(273)

To a stirred solution of compound 272 (300 mg, 0.569 mmol) in DMF (4 mL)was added Cs₂CO₃ (555 mg, 1.709 mmol) followed by tert-butylpiperazine-1-carboxylate (127 mg, 0.682 mmol). The reaction mixture waspurged with argon gas for 10 min followed by addition of Pd₂dba₃ (52 mg,0.0569 mmol) and BrettPhos (61 mg, 0.113). The reaction mixture wasstirred at 100° C. for 16 h. After completion (monitored by TLC), thereaction mixture was quenched with ice cold water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by combi flash chromatography (using a gradientmethod of 0-30% EtOAc/Heptane) to afford the title compound 273 (130 mg,36.11%) as an off white solid. TLC: 70% EtOAc/Heptane (R_(f). 0.5). LCMSCalculated for C28H33N5O8S2: 631.18; Found: 632.5 (M+H).

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(4-(piperazin-1-yl)thiazol-2-yl)benzo[d]isoxazol-3-yl)benzenesulfonamidehydrochloride (274)

To a stirred solution of compound 273 (130 mg, 0.2057 mmol) in DCM (2mL) at 0° C. was added 4M HCl in 1,4 Dioxane (0.5 mL, 2.057 mmol) Thereaction was allowed to stir at the room temperature for 2 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure and triturated with Et₂₀ to afford title compound274 (110 mg, HCl salt) as a yellow semi solid. TLC: 5% MeOH/DCM (R_(f).0.3). LCMS Calculated for C23H25N5O6S2: 531.12: Found: 532.20.

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(4-(4-propioloylpiperazin-1-yl)thiazol-2-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 274 (110 mg, 0.193 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.1 mL, 0.579 mmol), propiolic acid (16 mg,0.2316 mmol) followed by T₃P as a 50% solution in EtOAc (0.184 mL,0.2895 mmol). The reaction mixture was allowed to stir at roomtemperature for 2 h. After completion (monitored by TLC), the reactionmixture was concentrated under reduced pressure and crude was purifiedby using prep HPLC to afford the title compound (20 mg, 17.69%) as anoff-white solid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 foranalytical data).

Synthetic Example 119

Synthesis of tert-butyl 4-(2-bromopyridin-4-yl)piperazine-1-carboxylate(276)

To a stirred solution of compound 275 (1 g, 4.96 mmol) in ACN (5 mL) wasadded TEA (2 mL, 14.87 mmol) followed by tert-butylpiperazine-1-carboxylate (738 mg, 3.96 mmol) and CuI (94 mg, 0.495mmol). The resulting reaction mixture was stirred at 80° C. for 16 h.After completion (monitored by TLC), the reaction mixture was quenchedwith ice cold water and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by combi flashchromatography (using a gradient method 0-30% EtOAc/Heptane) to affordthe title compound 276 (250 mg, 14.79%) as an off-white solid. TLC: 50%EtOAc/Heptane (R_(f). 0.5). LCMS Calculated for C14H20BrN3O2: 341.07;Found: 342.5 (M+H).

Synthesis of tert-butyl4-(2-(3-((2,6-dimethoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)pyridin-4-yl)piperazine-1-carboxylate(277)

To a stirred solution of compound 204 (300 mg, 0.734 mmol) in 3:1mixture of 1,4 Dioxane: water (10 mL) was added K₂CO₃ (304 mg, 2.204mmol) followed by compound 276 (301 mg, 0.880 mmol). The reactionmixture was purged with argon gas for 10 min followed by addition ofPdCl₂dppf (53 mg, 0.0734 mmol). The reaction mixture was stirred at 80°C. for 16 h. After completion (monitored by TLC), the reaction mixturewas quenched with ice cold water and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bycombi flash chromatography (using a gradient method 0-20% EtOAc/Heptane)to afford the title compound 277 (100 mg, 21.78%) as an off-white solid.TLC: 50% EtOAc/Heptane (R_(f). 0.4). LCMS Calculated for C30H35N5O8S:625.22; Found: 626.2 (M+H).

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(4-(piperazin-1-yl)pyridin-2-yl)benzo[d]isoxazol-3-yl)benzenesulfonamidehydrochloride (278)

To a stirred solution compound 277 (100 mg, 0.1598 mmol) in DCM (2 mL)at 0° C. was added 4M HCl in 1,4 Dioxane (0.40 mL, 1.598 mmol). Thereaction was allowed to stir at the room temperature for 4 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure and triturated with Et₂₀ to afford title compound278 (85 mg, HCl salt) as an off-white semisolid. TLC: 5% MeOH/DCM(R_(f). 0.2). LCMS Calculated for C25H27N5O6S: 525.17: Found: 526.30.

Synthesis of2,6-dimethoxy-N-(4-methoxy-6-(4-(4-propioloylpiperazin-1-yl)pyridin-2-yl)benzo[d]isoxazol-3-yl)benzenesulfonamide

To a stirred solution of compound 278 (85 mg, 0.151 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.08 mL, 0.453 mmol), propiolic acid (12 mg,0.1812 mmol) followed by T₃P as a 50% solution in EtOAc (0.144 mL,0.2265 mmol). The reaction mixture was allowed to stir at roomtemperature for 2 h. After completion (monitored by TLC), the reactionmixture was concentrated under reduced pressure and crude was purifiedby using prep HPLC to afford the title compound (22 mg, 25.28%) as anoff-white solid. TLC: 5% MeOH/DCM (R_(f). 0.5). (See Table 1 foranalytical data).

Synthetic Example 120

Synthesis of 6-bromo-5-methylbenzo[d]isoxazol-3-amine (280)

To a stirred solution of compound 279 (2 g, 9.344 mmol) in a 7:1 mixtureof DMF: H₂O (8 mL) was added N-hydroxyacetamide (1.05 g, 14.016 mmol)followed by K₂CO₃ (3.87 g, 28.032 mmol). The reaction mixture wasallowed to stir at 60° C. for 16 h. After completion (monitored by TLC),the reaction mixture was quenched with ice cold water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The crude waspurified by using combi flash chromatography using gradient 40-80%EA/Heptane to afford the title compound 280 (2 g, 94.33%) as a brownsolid. TLC: 50% EtOAc/Heptane (R_(f). 0.50). LCMS Calculated forC8H7BrN2O: 225.97; Found: 226.02 (M+1).

Synthesis ofN-(6-bromo-5-methylbenzo[d]isoxazol-3-yl)-2,6-dimethoxybenzenesulfonamide(281)

To a stirred solution of compound 280 (1 g, 4.404 mmol) in THF (10 mL)was added 60% NaH (325 mg, 8.808 mmol) followed by2,6-dimethoxybenzenesulfonyl chloride (1.25 g, 5.284 mmol) at 0° C. Thereaction mixture was allowed to stir at the room temperature for 16 h.After completion (monitored by TLC), the reaction mixture was quenchedwith ice water and extracted with ethyl acetate. The organic layer wasdried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Thecrude compound was purified by combi flash chromatography (neutralalumina) to afford the title compound 281 (400 mg, 21.27%) as apale-yellow solid. TLC: 50 EtOAc (R_(f). 0.5). LCMS Calculated forC16H15BrN2O5S: 425.99; Found: 426.5 (M+1).

Synthesis of tert-butyl 4-(3-(3-((2,6-dimethoxyphenyl)sulfonamido)-5-methylbenzo[d]isoxazol-6-yl)phenyl)piperazine-1-carboxylate (282)

To a stirred solution of compound 281 (400 mg, 0.936 mmol) in 3:1mixture of 1,4 Dioxane:H₂O (10 mL) was added K₂CO₃ (388 mg, 2.808 mmol)and tert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate(436 mg, 1.123 mmol). The reaction mixture was purged with argon gas for10 min followed by addition of PdCl₂dppf (68 mg, 0.0936 mmol). Theresulting reaction mixture was stirred at 80° C. for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was quenched withice cold water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by combi flashchromatography (using a gradient 0-20% EtOAc/Heptane) to afford thetitle compound 282 (200 mg, 35.14%) as an off-white solid. TLC: 50%EtOAc/Heptane (R_(f). 0.4). LCMS Calculated for C31H36N4O7S: 608.23;Found: 609.2 (M+H).

Synthesis of 2,6-dimethoxy-N-(5-methyl-6-(3-(piperazin-1-yl) phenyl)benzo[d]isoxazol-3-yl) benzenesulfonamide hydrochloride (283)

To a stirred solution compound 282 (200 mg, 0.328 mmol) in DCM (2 mL) at0° C. was added 4M HCl in 1,4 Dioxane (0.8 mL, 3.328 mmol). The reactionwas allowed to stir at the room temperature for 4 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure and triturated with Et₂₀ to afford title compound 283 (150 mg,HCl salt) as off-white semi solid. TLC: 5% MeOH/DCM (R_(f). 0.2). LCMSCalculated for C26H28N4O5S: 508.18: Found: 509.30.

Synthesis of 2,6-dimethoxy-N-(5-methyl-6-(3-(4-propioloylpiperazin-1-yl)phenyl) benzo[d]isoxazol-3-yl) benzenesulfonamide

To a stirred solution of compound 283 (150 mg, 0.275 mmol) in DMF (2 mL)at 0° C. was added DIPEA (0.20 mL, 1.109 mmol), propiolic acid (25 mg,0.330 mmol) followed by T₃P as a 50% solution in EtOAc (0.35 mL, 0.550mmol). The reaction mixture was allowed to stir at room temperature for2 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure and crude was purified by using prepHPLC to afford the title compound (27 mg, 17.53%) as an off-white solid.TLC: 5% MeOH/DCM (R_(f). 0.5). See Table 1 for analytical data.

Synthetic Examples 121, 122, 123, 124 AND 125

Synthesis of 1-(methylsulfonyl)-1H-pyrazole (285)

To a stirred solution of pyrazole (2.0 g, 29.40 mmol) in DCM (20 mL) wasadded Et₃N (8.2 mL, 58.80 mmol) followed by methane sulfonyl chloride(2.49 mL, 32.2 mmol) and the resulting reaction mixture stirred at 0° C.for 1 h. After completion of the reaction (monitored by TLC), reactionmixture was concentrated under reduced pressure, diluted with ethylacetate and extracted. The organic layer was collected, washed withsaturated NaHCO₃ solution, washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound 285 (1.9 g, 44.25%) as a colorless liquid. TLC: 20%EtOAc/Heptane (R_(f). 0.4). ¹H NMR (400 MHz, CDCl₃): δ 8.01 (s, 1H),7.78 (s, 1H), 6.41 (s, 1H), 3.35 (s, 3H).

N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-1-methyl-1H-indazol-3-yl)-1-cyclohexylmethanesulfonamideStep 1: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-6-methoxybenzonitrile (286)

To a stirred solution of compound 15 (1.5 g, 8.20 mmol) in acetonitrile(50 mL) at room temperature was added Cs₂CO₃ (4.7 g, 14.70 mmol),followed by compound 285 (1.56 g, 10.70 mmol) and the resulting reactionmixture was heated at 70° C. for 4 h. After completion of the reaction(monitored by TLC), the reaction mixture was cooled to room temperature,diluted with water and extracted with ethyl acetate. The organic layerwas collected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bysilica gel (100-200 mesh) column chromatography using a gradient methodof 0-35% EtOAc/Heptane to afford the title compound 286 (1.7 g, 89%) asa yellow solid. TLC: 60% EtOAc/Heptane (R_(f). 0.4). ¹H NMR (400 MHz,DMSO-d₆): δ 7.89 (d, J=1.6 Hz, 1H), 7.53 (s, 1H), 6.99 (s, 1H), 6.69 (t,J=9.6 Hz, 1H), 6.33 (s, 1H), 5.43 (s, 2H), 3.90 (s, 3H). LCMS Calculatedfor C₁₂H₁₀FN₃O: 231.23; Found: 231.85 (M+)

Step 2: Synthesis of6-((1H-pyrazol-1-yl)methyl)-4-methoxy-1-methyl-1H-indazol-3-amine (287)

To a stirred solution of compound 286 (0.4 g, 1.70 mmol) in DMF: H₂O (11mL) was added K₂CO₃ (1.4 g, 10.20 mmol) followed by methyl hydrazine(aqueous solution) (0.3 mL, 5.17 mmol) and the resulting reactionmixture was heated at 70° C. for 16 h. After completion of the reaction(monitored by TLC), the reaction mixture was cooled to room temperature,diluted with water and extracted with ethyl acetate. The organic layerwas collected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified bysilica gel (100-200 mesh) column chromatography using a gradient methodof 0-50% EtOAc/Heptane to afford the title compound 286 (0.2 g, 44.94%)as an off-white solid. TLC: 80% EtOAc/Heptane (R_(f). 0.25). ¹H NMR (400MHz, DMSO-d₆): δ 7.83 (d, J=2.0 Hz, 1H), 7.47 (d, J=0.8 Hz, 1H), 6.69(s, 1H), 6.27 (d, J=1.6 Hz, 1H), 6.24 (s, 1H), 5.32 (s, 2H), 5.03 (s,2H), 3.80 (s, 3H), 3.62 (s, 3H). LCMS Calculated for C₁₃H₁₅N₅O: 257.30;Found: 258.35 (M+1)

Step 3: Synthesis ofN-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-1-methyl-1H-indazol-3-yl)-1-cyclohexylmethanesulfonamide(Synthetic Example 121)

To a stirred solution of compound 287 (130 mg, 0.50 mmol) in DCM (2 mL)at 0° C. was added Et₃N (0.43 mL, 0.30 mmol) followed by compound 3 (149mg, 0.76 mmol). The reaction mixture was stirred at the room temperaturefor 12 h. After completion of the reaction (monitored by TLC), reactionmixture was concentrated under reduced pressure and diluted with waterand extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by using prep HPLC toafford the title compound (21 mg, 9.9%) as an off-white solid. TLC: 80%EtOAc/Heptane (R_(f). 0.6). See Table 1 for analytical data.

Synthesis ofN-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-1-methyl-1H-indazol-3-yl)-2-fluorobenzenesulfonamide(Synthetic Example 122)

Step 4: To a stirred solution of compound 287 (100 mg, 0.038 mmol) inPyridine (3 mL) at 0° C. was added 2-fluorobenzenesulfonyl chloride (9mg, 0.046 mmol) and allowed to stir at the room temperature for 4 h. Thereaction mixture was concentrated under reduced pressure and dilutedwith water and extracted with ethyl acetate. The organic layer wascollected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude compound was purified byusing prep HPLC to afford the title compound (36 mg, 22.27%) as anoff-white solid. TLC: 80% EtOAc/Heptane (R_(f). 0.4). See Table 1 foranalytical data.

Synthesis ofN-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-1-methyl-1H-indazol-3-yl)-2,6-dimethoxybenzenesulfonamideSynthetic Example 123)

Step 5: To a stirred solution of compound 287 (160 mg, 0.62 mmol) inpyridine (5 mL) at 0° C. was added compound 5 (162 mg, 0.68 mmol) andthe resulting reaction mixture was allowed to stir at the roomtemperature for 2 h. After completion (monitored by TLC), the reactionmixture was concentrated under vacuum, the residue was quenched withwater and extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by using prep HPLC toafford the title compound (60 mg, 21.1%) as an off-white solid. TLC: 80%EtOAc/Heptane (R_(f). 0.3). See Table 1 for analytical data.

Synthesis ofN-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-1H-indazol-3-yl)-2-fluorobenzenesulfonamide(Synthetic Example 124)

Step 6: Synthesis of6-((1H-pyrazol-1-yl)methyl)-4-methoxy-1H-indazol-3-amine (288):

To a stirred solution of compound 286 (0.6 g, 2.59 mmol) in DMF: H₂O (11mL) was added K₂CO₃ (2.14 g, 15.5 mmol) followed by hydrazine hydrate[1M in THF] (7.7 mL, 7.7 mmol) and the reaction mixture was heated at70° C. for 16 h. After completion of the reaction (monitored by TLC),the reaction mixture was cooled to room temperature, diluted with waterand extracted with ethyl acetate. The organic layer was collected,washed with brine, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude compound was purified by silica gel (100-200mesh) column chromatography using a gradient method of 0-60%EtOAc/Heptane to afford the title compound 288 (0.3 g, 47.5%) as ayellow solid. TLC: 80% EtOAc/Heptane (R_(f). 0.25). ¹H NMR (400 MHz,DMSO-d₆): δ 11.34 (s, 1H), 7.82 (s, 1H), 7.47 (s, 1H), 6.48 (s, 1H),6.27 (t, J=1.6 Hz, 1H), 6.24 (s, 1H), 5.33 (s, 2H), 4.95 (s, 2H), 3.83(s, 3H). LCMS Calculated for C₁₂H₁₃N₅O: 243.27; Found: 243.95 (M+).

Step 7: Synthesis ofN-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-1H-indazol-3-yl)-2-fluorobenzenesulfonamide(Synthetic Example 124): To a stirred solution of compound 288 (100 mg,0.41 mmol) in Pyridine (3 mL) at 0° C. was added compound 6 (80 mg, 0.41mmol) and the reaction was allowed to stir at the room temperature for12 h. After completion (monitored by TLC), reaction mixture wasconcentrated under high vacuum. The residue was quenched with water andextracted with ethyl acetate. The organic layer was collected, washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by using prep HPLC to affordthe title compound (25 mg, 15.14%) as an off-white solid. TLC: 80%EtOAc/Heptane (R_(f). 0.5). See Table 1 for analytical data.

Synthesis ofN-(6-((1H-pyrazol-1-yl)methyl)-4-methoxy-1H-indazol-3-yl)-2,6-dimethoxybenzenesulfonamide(Synthetic Example 125)

Step 8: To a stirred solution of compound 17 (160 mg, 0.65 mmol) inpyridine (5 mL) at 0° C. was added compound 5 (170 mg, 0.72 mmol) andthe reaction was allowed to stir at the room temperature for 2 h. Aftercompletion (monitored by TLC), reaction mixture was concentrated underhigh vacuum. The residue was quenched with water and extracted withethyl acetate. The organic layer was collected, washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by using prep HPLC to afford the title compound(38 mg, 13%) as an off-white solid. TLC: 80% EtOAc/Heptane (R_(f).0.35). See Table 1 for analytical data.

Synthetic Example 126

Step 1: Synthesis of 1-(methylsulfonyl)-1H-pyrazole-4-carbonitrile (290)

To a stirred solution of compound 289 (2.0 g, 21.50 mmol) in DCM (20 mL)was added Et₃N (4.5 mL, 32.2 mmol) followed by methane sulfonyl chloride(2.49 mL, 32.2 mmol) and the resulting reaction mixture stirred at 0° C.for 1 h. After completion of the reaction (monitored by TLC), thereaction mixture was concentrated under reduced pressure, diluted withethyl acetate and extracted. The organic layer was collected; washedwith saturated NaHCO₃ solution; washed with brine; dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford the titlecompound 290 (2.1 g, 57.10%) as a white solid. TLC: 30% EtOAc/Heptane(R_(f). 0.3). ¹H NMR (400 MHz, CDCl₃): δ 8.48 (s, 1H), 8.05 (s, 1H),3.44 (s, 3H).

Step 2: Synthesis of1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazole-4-carbonitrile (291)

To a stirred solution of compound 15 (0.4 g, 2.20 mmol) in acetonitrile(5 mL) was added Cs₂CO₃ (1.0 g, 3.31 mmol) followed by compound 290(0.45 g, 2.65 mmol) and the resulting reaction mixture was heated at 70°C. for 4 h. After completion of the reaction (monitored by TLC), thereaction mixture was cooled to room temperature, diluted with ethylacetate and extracted. The organic layer was collected, washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by silica gel (100-200 mesh)column chromatography using a gradient method of 0-50% EtOAc/Heptane toafford the title compound 291 (0.27 g, 47.72%) as a yellow solid. TLC:80% EtOAc/Heptane (R_(f). 0.45). ¹H NMR (400 MHz, DMSO-d₆): δ 8.71 (s,1H), 8.13 (s, 1H), 7.08 (s, 1H), 6.84 (d, J=11.2 Hz, 1H), 5.50 (s, 2H),3.94 (s, 3H).

Step 3: Synthesis of1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazole-4-carbonitrile(292)

To a stirred solution of compound 291 (0.27 g, 1.05 mmol) in DMF (3 mL)was added acetohydroxamic acid (0.237 g, 3.16 mmol) followed by ^(t)BuOK(0.35 g, 3.16 mmol) and the reaction mixture was allowed to stir at 65°C. for 12 h. After completion of the reaction (monitored by TLC),reaction mixture was cooled to room temperature, diluted with ethylacetate and extracted. The organic layer was collected, washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by silica gel (100-200 mesh)column chromatography using a gradient method of 0-50% EtOAc/Heptane toafford the title compound to afford the title crude compound 292 (0.18g, 63.44%) as a brown solid. TLC: 80% EtOAc/Heptane (R_(f). 0.35). ¹HNMR (400 MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.11 (s, 1H), 6.84 (s, 1H), 6.69(s, 1H), 5.97 (s, 2H), 5.47 (s, 2H), 3.88 (s, 3H). LCMS Calculated forC₁₃H₁₁N₅O₂: 269.26; Found: 269.90

Step 4: Synthesis ofN-(6-((4-cyano-1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-1-cyclohexylmethanesulfonamide(Synthetic Example 126)

To a stirred solution of compound 292 (100 mg, 0.37 mmol) in DCM (1 mL)at 0° C. was added Et₃N (0.05 mL, 0.40 mmol) followed by compound 3 (80mg, 0.40 mmol) and the reaction was allowed to stir at room temperaturefor 12 h. After completion of the reaction (monitored by TLC), reactionmixture was again cooled to room temperature, diluted with DCM andextracted. The organic layer was collected, washed with brine, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudecompound was purified by using prep HPLC to afford the title compound (7mg, 4.4%) as an off-white solid. TLC: 80% EtOAc/Heptane (Rf: 0.35). SeeTable 1 for analytical data.

Synthetic Example 127

Step 1: Synthesis of (2-chloro-6-methoxypyridin-4-yl)methanol (294)

To a stirred solution of compound 293 (2 g, 9.95 mmol) in THF (20 mL)was added LiBH₄ (0.647 g, 29.8 mmol) at 0° C. and the reaction mixturewas allowed to stir at the room temperature for 4 h. The progress of thereaction was monitored by TLC. After completion, the mixture wasacidified with 1N HCl and extracted with ethyl acetate. The organiclayer was collected, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford the title compound 294(1.1 g, 96.32%) as a yellow solid. TLC: 30% EtOAc/Heptane (R_(f). 0.3);¹H NMR (400 MHz, DMSO-d₆): δ 7.00 (s, 1H), 6.74 (s, 1H), 5.50 (broad s,1H), 4.49 (s, 2H), 3.83 (s, 3H). LCMS Calculated for C₇H₈ClNO₂: 173.60;Found: 174.2 (M+1).

Step 2: Synthesis of4-((1H-pyrazol-1-yl)methyl)-2-chloro-6-methoxypyridine (295)

To a stirred solution of compound 294 (0.5 g, 2.89 mmol) in CH₃CN (5 mL)was added Cs₂CO₃ (2.8 g, 8.67 mmol) followed by compound 285 (0.63 g,4.33 mmol) and the resulting mixture was heated at 70° C. for 4 h. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasfiltered through a pad of Celite and washed with ethyl acetate. Thefiltrate was collected, washed with brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude compound was purifiedby combi flash column chromatography using a gradient method of 0-30%EtOAc/Heptane to afford the title compound 295 (1 g, 71%) as a yellowsolid. TLC: 50% EtOAc/Heptane (R_(f). 0.4). ¹H NMR (400 MHz, DMSO-d₆): δ7.61 (s, 1H), 7.45 (d, J=2.0 Hz, 1H), 6.66 (s, 1H), 6.36 (s, 2H), 5.29(s, 2H), 3.91 (s, 3H). LCMS Calculated for C₁₀H₁₀ClN₃: 223.66; Found:223.80 (M+).

Step 3: Synthesis of4-((1H-pyrazol-1-yl)methyl)-2-hydrazineyl-6-methoxypyridine (296)

To a stirred solution of compound 295 (1.0 g, 4.48 mmol) in ethanol (10mL) was added hydrazine hydrate (286 mg, 8.96 mmol) and the reactionmixture was allowed to stir at 80° C. for 16 h. After completion(monitored by TLC), the reaction mixture was concentrated under reducedpressure to afford the title compound 296 (0.4g, 40%) as a brown gummysolid. TLC: 50% EtOAc/Heptane (R_(f). 0.2); ¹H NMR (400 MHz, DMSO-d₆): δ7.79 (s, 1H), 7.47 (s, 1H), 7.34 (s, 1H), 6.23 (s, 1H), 6.07 (s, 1H),5.64 (s, 1H), 5.18 (s, 2H), 4.06 (s, 2H), 3.72 (s, 3H). LCMS Calculatedfor C10H₁₃N₅O: 219.25; Found: 219.95 (M+).

Step 4: Synthesis of7-((1H-pyrazol-1-yl)methyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-amine(297)

To a stirred solution of compound 296 (200 mg, 0.82 mmol) in a 9:1mixture of EtOH: H₂O (9:1) (2 mL) was added a pre-dissolved solution ofcyanogen bromide (104 mg, 0.98 mmol) in EtOH: H₂O (1:1, 2 mL) at 0° C.and the reaction mixture was allowed to stir at the room temperature for16 h. The progress of reaction was monitored by TLC and LCMS. Aftercompletion, the reaction mixture was concentrated under reduced pressureto get crude compound which was triturated with n-pentane/EtOAc anddried under vacuum to afford the title compound 297 (110 mg, 55.0%) as abrown solid. TLC: 80% EtOAc/Heptane (R_(f). 0.15). ¹H NMR (400 MHz,DMSO-d₆): δ 7.93 (s, 1H), 7.74-7.46 (m, 3H), 6.57 (s, 1H), 6.37 (s, 1H),6.32 (s, 1H), 5.42 (s, 2H), 4.03 (s, 3H). LCMS Calculated for C₁₁H₁₂N₆O:244.26; Found: 245.2 (M+1).

Step 5: Synthesis ofN-(7-((1H-pyrazol-1-yl)methyl)-5-methoxy-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-cyclohexylmethanesulfonamide(Synthetic Example 127)

To a stirred solution of compound 297 (150 mg, 0.61 mmol) in THF: DCM(1:1, 1 mL) was added Et₃N (0.23 mL, 1.83 mmol) followed by compound 3(140 mg, 0.737 mmol) and the reaction mixture was allowed to stir at 60°C. for 16 h. The progress of the reaction was monitored by LCMS and TLC.After completion, the reaction mixture was diluted with ethyl acetateand extracted. The combined organic layer was collected, washed withbrine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The crude compound was purified by prep HPLC to afford thetitle compound (7 mg, 2.8%) as a white solid. TLC: 5% MeOH/DCM (R_(f).0.25). See Table 1 for analytical data.

Synthetic Example 128, 129

The synthesis of Synthetic Example 128 was described in Scheme 14,compound 48. See Table 1 for analytical data.

To a stirred solution of compound of Synthetic Example 128 (80 mg, 0.18mmol) in DMF (2.5 mL) at 0° C. was added DIPEA (0.12 mL, 0.72 mmol),followed by T₃P (0.17 mL, 0.27 mmol). The reaction was allowed to stirat room temperature for 20 min. After that, a pre-dissolved solution ofpropionic acid (13 mg, 0.18 mmol) in DMF (0.5 mL) was added in adrop-wise manner and the reaction was allowed to stir at roomtemperature for 16 h. After completion (monitored by TLC), the solventwas concentrated under vacuum. The residue was quenched with water andextracted with ethyl acetate. The organic layer was collected, washedwith brine, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford the crude product which was purified by usingprep-HPLC to obtain inseparable mixture of isomers. The isomers werefurther separated by using Chiral HPLC (Method: Chiral-Met-B 30%_1.0mL/cm; Mobile phase: A; 0.1% DEA in n-Hexane; B; DCM:MEOH (50:50) A:B,70:30; Injection volume: 5 μL; Flow rate: 1.0 mL/min; Column: CHIRAL PAKIG (250*4.6 mm, 5 μm); Duration up to 25 min.) to afford the titlecompound of Synthetic Example 129 (18 mg, 20%) as an off-white solid.TLC: 100% EtOAc (R_(f). 0.5). Minor isomer was not isolated in enoughquantity due to merged impurities. See Table 1 for analytical data.

Synthetic Example 130

The synthesis of Synthetic Example 130 was described in Scheme 7,compound 23a. The crude compound was purified by prep HPLC to afford thetitle compound as an off-white solid. See Table 1 for analytical data.

TABLE 1 Analytical data for final compounds Mass Spec. Syn. Found (m/z)/¹H-NMR Ex. Mass Spec. (400 M Hz, DMSO-d₆, unless otherwise No.Calculated stated)  1 500.05 δ 10.41 (s, 1H), 7.78 (d, J = 6.4 Hz, 1H),(M + 1)/ 6.98-6.95 (m, 1H), 6.85-6.78 (m, 1H), 499.59 for 6.69-6.50 (m,1H), 6.21 (dd, J = 16.8, 6.8 C₂₄H₂₉N₅O₅S Hz, 1H), 5.74 (d, J = 10.4 Hz,1H), 5.45- 5.38 (m, 2H), 4.79-4.65 (m, 2H), 4.45 (d, J = 12.4 Hz, 2H),3.91 (s, 3H), 3.37 (d, J = 6.0 Hz, 2H), 2.01-1.92 (m, 1H), 1.86 (d, J =11.6 Hz, 2H), 1.64 (d, J = 12.4 Hz, 1H), 1.57 (d, J = 12.0 Hz, 2H),1.28-1.05 (m, 5H). ¹H NMR hints for mixture of regio-isomers. Thechemical shift values for major isomer have been captured.  2 498.10 δ10.39 (d, J = 3.6 Hz, 1H), 7.78 (s, 1H), (M + 1)/ 6.99 (d, J = 3.6 Hz,1H), 6.83 (m, J = 13.2 497.57 for Hz, 1H), 5.45-5.40 (m, 2H), 4.78-4.66(m, C₂₄H₂₇N₅O₅S 2H), 4.57-4.55 (m, 1H), 4.46-4.39 (m, 2H), 3.91 (s, 3H),3.37 (d, J = 6.0 Hz, 2H), 2.01-1.94 (m, 1H), 1.85 (d, J = 11.6 Hz, 2H),1.64 (d, J = 12.4 Hz, 2H), 1.58 (d, J = 12.4 Hz, 1H), 1.28-1.05 (m, 5H).¹H NMR indicates mixture of regio-isomers. The chemical shift values formajor isomer have been captured.  3 555.35 (M + 1)/ δ 10.42 (broad s,1H), 7.77 (d, J = 1.6 Hz, 554.67 for 1H), 6.89 (s, 1H), 6.76 (s, 1H),5.42 (s, C₂₇H₃₄N₆O₅S: 2H), 4.72 (d, J = 2.8 Hz, 2H), 4.43 (s, 2H), 3.88(s, 3H), 3.51 (s, 2H), 3.30-3.22 (m, 2H), 2.24 (s, 6H), 1.95-1.84 (m,3H), 1.67- 1.52 (m, 3H), 1.24-1.03 (s, 5H). ¹H NMR hints for minorisomer (<5%).  4 488.05 (M + 1)/ δ 8.36 (s, 1H), 8.15 (s, 1H), 7.74 (s,1H), 487.05 for 7.40 (s, 1H), 6.68 (s, 1H), 6.56 (s, 1H), C₂₃H₂₉N₅O₅S6.26-6.15 (m, 1H), 6.12-6.04 (m, 1H), 5.57 (d, J = 9.6 Hz, 1H), 5.32 (s,2H), 4.18 (d, J = 4.8 Hz, 2H), 3.81 (s, 3H), 2.99 (broad s, 2H),2.04-1.72 (m, 3H), 1.64- 1.49 (m, 3H), 1.31-1.04 (m, 3H), 1.02- 0.89 (m,2H).  5 486.05 (M + 1)/ δ 10.37 (s, 1H), 9.04 (t, J = 5.6 Hz, 1H),485.56 for 7.76 (s, 1H), 7.40 (s, 1H), 6.91 (s, 1H), C₂₃H₂₇N₅O₅S 6.77(s, 1H), 5.40 (s, 2H), 4.13 (d, J = 5.6 Hz, 2H), 4.11 (s, 1H), 3.89 (s,3H), 3.30 (merged m, 2H), 1.99-1.92 (m, 1H), 1.86 (d, J = 10.4 Hz, 2H),1.66-1.62 (m, 2H), 1.58 (d, J = 11.2 Hz, 1H), 1.28-1.14 (m, 2H),1.11-1.04 (m, 3H).  6 524.05 (M + 1)/ δ 10.39 (s, 1H), 7.79 (s, 1H),7.57 (t, J = 523.62 for 5.6 Hz, 1H), 7.43 (s, 1H), 6.90 (s, 1H),C₂₂H₂₉N₅O₆S₂ 6.80 (s, 1H), 6.63 (dd, J = 16.4, 1.2 Hz, 1H), 6.01 (d, J =16.8 Hz, 1H), 5.91 (d, J = 10.0 Hz, 1H), 5.42 (s, 2H), 3.92 (d, J = 6.0Hz, 2H), 3.88 (s, 3H), 3.37 (d, J = 6.0 Hz, 2H), 2.03-1.92 (m, 1H), 1.86(d, J = 12.4 Hz, 2H), 1.65 (d, J = 12.8 Hz, 2H), 1.57 (d, J = 13.2 Hz,1H), 1.28-1.04 (m, 5H).  7 488.05 (M + 1)/ δ 10.37 (s, 1H), 8.47-8.42(m, 1H), 7.78 487.05 for (d, J = 2.0 Hz, 1H), 6.89 (s, 1H), 6.75 (s,C₂₃H₂₉N₅O₅S 1H), 6.26-6.02 (m, 3H), 5.55 (dd, J = 9.6, 2.0 Hz, 1H), 5.37(s, 2H), 4.26 (d, J = 5.6 Hz, 2H), 3.86 (s, 3H), 3.35-3.33 (m, 2H),1.96-1.88 (m, 1H), 1.83 (d, J = 12.0 Hz, 2H), 1.64-1.52 (m, 3H),1.25-1.04 (m, 5H). ¹H NMR hints for mixture of regio- isomers. Thechemical shift values for major isomer have been captured.  8 486.10(M + 1)/ δ 10.37 (s, 1H), 9.11 (t, J = 6.0 Hz, 1H), 485.56 for 7.80 (d,J = 2.4 Hz, 1H), 6.92 (s, 1H), 6.77 C₂₃H₂₇N₅O₅S (s, 1H), 6.16 (d, J =2.4 Hz, 1H), 5.40 (d, J = 6.4 Hz, 2H), 4.23 (d, J = 6.0 Hz, 2H), 4.12(s, 1H), 3.89 (s, 3H), 3.35 (d, J = 6.4 Hz, 2H), 2.02-1.92 (m, 1H), 1.86(d, J = 6.4 Hz, 2H), 1.68-1.54 (m, 3H), 1.29-1.04 (m, 5H). ¹H NMR hintsfor single isomer and the structure further confirmed from its nOestudy.  9 490.10 (M + 1)/ δ 10.38 (s, 1H), 8.11 (t, J = 5.6 Hz, 1H),489.59 for 7.79 (d, J = 2.0 Hz, 1H), 6.92 (s, 1H), 6.78 C₂₃H₃₁N₅O₅S (s,1H), 6.15 (d, J = 2.4 Hz, 1H), 5.39 (s, 2H), 4.19 (d, J = 5.6 Hz, 2H),3.90 (s, 3H), 3.36 (d, J = 6.0 Hz, 2H), 2.09 (q, J = 7.6 Hz, 2H),2.02-1.93 (m, 1H), 1.86 (d, J = 11.2 Hz, 2H), 1.68-1.54 (m, 3H), 1.29-1.02 (m, 5H), 0.99 (t, J = 7.6 Hz, 3H). ¹H NMR indicates single isomerand the structure further confirmed from its nOe study. 10 401.15 (M −1)/ δ 8.68 (t, J = 6.0 Hz, 1H), 7.98 (t, J = 6.4 402.40 for Hz, 1H),7.83-7.68 (m, 3H), 7.51 (s, 1H), C₁₉H₁₅FN₂O₅S 7.41 (q, J = 8.0 Hz, 2H),7.26 (d, J = 7.6 Hz, 1H), 6.28 (dd, J = 16.8, 10.0 Hz, 1H), 6.13 (dd, J= 16.4, 2.0 Hz, 1H), 5.63 (dd, J = 10.0, 2.4 Hz, 1H), 4.48 (d, J = 5.6Hz, 2H). NH proton not observed. 11 401.00 (M + 1)/ δ 9.32 (t, J = 6.0Hz, 1H), 7.99 (t, J = 6.4 400.38 for Hz, 1H), 7.85 (broad s, 1H),7.79-7.71 (m, C₁₉H₁₃FN₂O₅S 2H), 7.50 (s, 1H), 7.43 (q, J = 8.0 Hz, 2H),7.25 (d, J = 8.0 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H), 4.18 (s, 1H). NHproton not observed. 12 468.91 (M + 1)/ δ 10.79 (broad s, 1H), 10.26(broad s, 1H), 468.50 for 8.74 (t, J = 5.6 Hz, 1H), 8.60 (d, J = 4.8C₂₃H₂₁FN₄O₄S Hz, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.81 (t,J = 6.0, 1H), 7.73-7.64 (m, 1H), 7.57 (s, 1H), 7.40 (t, J = 9.2 Hz, 1H),7.30 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 4.4 Hz, 1H), 6.32 (dd, J = 16.8,10.0 Hz, 1H), 6.16 (dd, J = 17.2, 2.0 Hz, 1H), 5.67 (dd, J = 10.4, 2.0Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 2.41 (s, 3H). 13 466.97 (M + 1)/ δ10.82 (broad s, 1H), 10.32 (broad s, 1H), 466.19 for 9.39 (t, J = 6.0Hz, 1H), 8.62 (d, J = 5.2 C₂₃H₁₉FN₄O₄S Hz, 1H), 8.17 (s, 1H), 8.05 (s,1H), 7.85- 7.79 (m, 2H), 7.67 (q, J = 6.4 Hz, 1H), 7.58 (s, 1H), 7.40(t, J = 9.2 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 5.2 Hz, 1H),4.40 (d, J = 6.0 Hz, 2H), 4.26 (s, 1H), 2.41 (s, 3H). 14 512.15 (M − 1)/_(CD₃OD): 8.09 (dt, J = 7.2, 1.2 Hz, 1H), 513.54 for 7.76-7.65 (m, 3H),7.53 (s, 1H), 7.42 (t, C₂₅H₂₄FN₃O₆S J = 7.2 Hz, 1H), 7.31-7-29 (m, 2H),6.77- 6.74 (m, 1H), 6.18-6.16 (m, 1H), 5.72 (dd, J = 10.4, 2.0 Hz, 1H),4.56 (d, J = 13.2 Hz, 1H), 4.49 (s, 2H), 4.15 (d, J = 14.0 Hz, 1H), 3.17(t, J = 13.2 Hz, 1H), 2.79 (t, J = 12.4 Hz, 1H), 2.60-2.51 (m, 1H), 1.88(d, J = 11.2 Hz, 2H), 1.71-1.62 (m, 2H). 15 509.07 (M − 1)/ δ 10.81(brs, 1H), 9.15 (brs, 1H), 8.74 (s, 510.57 for 1H), 8.60 (d, J = 4.8 Hz,1H), 8.18 (s, 1H), C₂₅H₂₆N₄O₆S 8.03 (s, 1H), 7.86 (s, 1H), 7.57 (s, 1H),7.48 (t, J = 8.4 Hz, 1H), 7.24 (d, J = 4.8 Hz, 1H), 6.74 (d, J = 8.0 Hz,2H), 6.35- 6.28 (m, 1H), 6.15 (d, J = 16.8 Hz, 1H), 5.68 (d, J = 10.8Hz, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.87 (s, 6H), 2.40 (s, 3H) 16 509.2(M + 1)/ δ 9.38 (brs, 1H), 8.61 (d, J = 4.8 Hz, 1H), 508.55 for 8.18 (s,1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.58 (s, 1H), 7.48 (t, J = 8.4 Hz, 1H),7.23 C₂₅H₂₄N₄O₆S (d, J = 4.8 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H), 4.40 (d,J = 5.6 Hz, 2H), 4.25 (s, 1H) 3.86 (s, 6H), 2.40 (s, 3H). 17 522.05 (M +1)/ δ 7.87-7.80 (m, 2H), 7.68 (t, J = 6.0 Hz, 521.54 for 2H), 7.62 (brs,1H), 7.31 (brs, 1H), 6.77 C₂₁H₂₀FN₅O₆S₂ (brs, 1H), 6.68-6.56 (m, 1H),6.24 (d, J = 2.0 Hz, 1H), 5.95 (d, J = 3.6 Hz, 1H), 5.82 (d, J = 6.0 Hz,1H), 5.35 (s, 2H), 3.99 (d, J = 6.4 Hz, 2H), 3.79 (s, 3H). ¹H-NMR didn'tshow exchangeable protons and further indicates a mixture of regio-isomers. The chemical shift values for major isomer have been capturedand the structure further confirmed from its nOe study. 18 485.93 (M +1)/ δ 11.28 (br s, 1H), 8.45 (t, J = 5.2 Hz, 1H), 485.49 for 7.88 (t, J= 1.6 Hz, 1H), 7.85 (s, 1H), 7.73 C₂₂H₂₀FN₅O₅S (q, J = 5.6 Hz, 1H),7.46-7.36 (m, 2H), 6.89 (s, 1H), 6.73 (s, 1H), 6.27-6.07 (m, 3H), 5.59(dd, J = 10.0, 6.4 Hz, 1H), 5.37 (s, 2H), 4.28 (d, J = 5.6 Hz, 2H), 3.77(s, 3H). ¹H-NMR indicates the single regioisomer and the structure wasfurther confirmed from its nOe study. 19 564.3 (M + 1)/ δ 9.58 (s, 1H),7.82 (d, J = 2.0 Hz, 1H), 563.60 for 7.69 (t, J = 6.0 Hz, 1H), 7.49 (t,J = 8.4 C₂₃H₂₅N₅O₈S₂ Hz, 1H), 6.84 (s, 1H), 6.77 (d, J = 8.4 Hz, 3H),6.63-6.56 (m, 1H), 6.25 (d, J = 2.0 Hz, 1H), 5.97 (d, J = 16.4 Hz, 1H),5.82 (d, J = 10.0 Hz, 1H), 5.38 (s, 2H), 3.99 (d, J = 6.0 Hz, 2H), 3.87(s, 3H), 3.56 (s, 6H, merged). ¹H-NMR indicates a single regioisomer. 20482.2 (M + 1)/ δ 10.56 (s, 1H), 8.46 (t, J = 2.0 Hz, 1H), 481.53 for7.82 (d, J = 2.0 Hz, 1H), 7.39-7.35 (m, 5H, C₂₃H₂₃N₅O₅S merged), 6.96(s, 1H), 6.78 (s, 1H), 6.29- 6.18 (m, 1H), 6.12 (d, J = 2.4 Hz, 2H),5.59 (dd, J = 10.0, 2.0 Hz, 1H), 5.41 (s, 2H), 4.77 (s, 2H), 4.30 (d, J= 5.6 Hz, 2H), 3.86 (s, 3H). ¹H-NMR indicates a single regioisomer andthe structure further confirmed from its nOe study. 21 518.2 (M + 1)/ δ7.81 (d, J = 2.0 Hz, 1H), 7.71 (t, J = 6.4 517.58 for Hz, 1H), 7.25-7.18(m, 5H), 6.64 (d, J = C₂₂H₂₃N₅O₆S₂ 2.0 Hz, 1H), 6.61-6.57 (m, 1H), 6.51(s, 1H), 6.24 (d, J = 2.0 Hz, 1H), 5.98 (d, J = 16.4 Hz, 1H), 5.83 (d, J= 10.0 Hz, 1H), 5.29 (s, 2H), 4.30 (brs, 2H), 4.01 (d, J = 6.0 Hz, 2H),3.84 (s, 3H). ¹H-NMR didn't show one exchangeable proton and indicates asingle regioisomer. 22 534.2 (M + 1)/ δ 10.11 (s, 1H), 7.80 (dd, J =9.2, 2.4 Hz, 533.57 for 1H), 7.67 (d, J = 6.0 Hz, 1H), 7.62 (t, J =C₂₂H₂₃N₅O₇S₂ 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 7.6 Hz,1H), 6.84 (s, 1H), 6.75 (s, 1H), 6.63-6.56 (m, 1H), 6.24 (d, J = 2.0 Hz,1H), 5.98 (d, J = 16.4 Hz, 1H), 5.83 (d, J = 10.0 Hz, 1H), 5.37 (s, 2H),3.99 (d, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H). ¹H-NMR didn't showone exchangeable proton and indicates a single regioisomer. 23 506.2(M + 1)/ δ 10.37 (s, 1H), 8.92 (t, J = 5.6 Hz, 1H), 505.57 for 7.79 (d,J = 2.0 Hz, 1H), 6.91 (s, 1H), 6.75 C₂₃H₂₈FN₅O₅S (s, 1H), 6.17 (d, J =2.0 Hz, 1H), 5.59-5.46 (m, 1H), 5.39 (s, 2H), 5.27 (dd, J = 16.0, 3.6Hz, 1H), 4.31 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H), 3.34 (t, J = 6.4 Hz,2H), 1.94-1.90 (m, 1H), 1.88 (d, J = 12.8 Hz, 2H), 1.65 (d, J = 3.2 Hz,2H), 1.62-1.56 (m, 1H), 1.27-1.03 (m, 5H). ¹H-NMR indicates a singleregioisomer and the structure further confirmed from its nOe study. 24524.00 (M + 1)/ δ 10.37 (brs, 1H), 7.83 (d, J = 2.0 Hz, 1H), 523.62 for7.69 (t, J = 6.0 Hz, 1H), 6.87 (s, 1H), 6.76 C₂₂H₂₉N₅O₆S₂ (s, 1H),6.66-6.57 (m, 1H), 6.26 (d, J = 2.4 Hz, 1H), 5.98 (d, J = 16.8 Hz, 1H),5.85 (d, J = 10.0 Hz, 1H), 5.39 (s, 2H), 4.00 (d, J = 6.0 Hz, 2H), 3.89(s, 3H), 1.97-1.84 (m, 2H), 1.65-1.55 (m, 2H), 1.27-1.03 (m, 9H). ¹H-NMRshowed traces of impurities and a mixture of regio-isomers. The chemicalshift values for major isomer have been captured.  25a 538.05 (M + 1)/ δ9.59 (brs, 1H), 7.47 (s, 1H), 7.35 (s, 1H), 537.55 for 6.94 (d, J = 12.8Hz, 1H), 6.78-6.74 (m, C₂₅H₂₃N₅O₇S 3H), 5.39 (d, J = 9.6 Hz, 2H), 4.75(s, 1H), 4.64 (s, 1H), 4.56 (d, J = 3.6 Hz, 1H), 4.42 (s, 1H), 4.38 (s,1H), 3.89 (d, J = 1.6 Hz, 3H), 3.75 (s, 6H, merged). ¹H-NMR indicates asingle regioisomer and the structure further confirmed from its nOestudy.  25b 538.10 (M + 1)/ δ 9.59 (br s, 1H), 7.75 (s, 1H), 7.48 (t, J= 537.55 for 6.8 Hz, 1H), 6.89 (s, 1H), 6.80 (s, 1H), C₂₅H₂₃N₅O₇S 6.76(d, J = 8.4 Hz, 2H), 5.41 (s, 2H), 4.71 (d, J = 2.0 Hz, 2H), 4.56 (d, J= 6.4 Hz, 1H), 4.42 (s, 2H), 3.78 (s, 3H), 3.70 (s, 6H, merged). ¹H-NMRindicates a single regioisomer and the structure further confirmed fromits nOe study.  26a 508.3 (M + 1)/ δ 10.13 (s, 1H), 7.81 (d, J = 6.8 Hz,1H), 507.52 for 7.62 (t, J = 7.6 Hz, 1H), 7.35 (s, 1H), 7.18 C₂₄H₂₁N₅O₆S(d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 11.6 Hz,1H), 6.77 (s, 1H), 5.40 (d, J = 10.0 Hz, 2H), 4.76 (s, 1H), 4.65 (s,1H), 4.56 (d, J = 4.4 Hz, 1H), 4.43 (s, 1H), 4.38 (s, 1H), 3.84 (d, J =2.4 Hz, 3H), 3.78 (s, 3H). ¹H-NMR indicates a single regioisomer.  26b506.01 (M − 1)/ δ 10.12 (s, 1H), 7.80 (dd, J = 8.0, 2.0 Hz, 507.52 for1H), 7.75 (s, 1H), 7.62 (t, J = 7.2 Hz, 1H), C₂₄H₂₁N₅O₆S 7.20 (d, J =8.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 6.92 (s, 1H), 6.80 (s, 1H), 5.41(s, 2H), 4.70 (d, J = 1.2 Hz, 2H), 4.56 (d, J = 6.4 Hz, 1H), 4.42 (s,2H), 3.84 (s, 3H), 3.79 (s, 3H). ¹H-NMR indicates a single regioisomer. 27a 446.0 (M + 1)/ δ 10.12 (br s, 1H), 7.80 (dd, J = 8.0, 2.0 545.59for Hz, 1H), 7.71 (s, 1H), 7.60 (t, J = 8.0 Hz, C₂₃H₂₃N₅O₇S₂ 1H), 7.18(d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.96-6.89 (m, 2H), 6.78(s, 1H), 6.16 (s, 1H), 6.11 (d, J = 10.0 Hz, 1H), 5.40 (s, 2H), 4.32 (d,J = 2.8 Hz, 4H), 3.83 (s, 3H), 3.78 (s, 3H). ¹H-NMR indicates a singleregioisomer and the structure further confirmed from its nOe study.  27b546.0 (M + 1)/ δ 10.14 (s, 1H), 7.81 (dd, J = 8.0, 1.6 Hz, 545.59 for1H), 7.62 (t, J = 8.0 Hz, 1H), 7.31 (s, 1H), C₂₃H₂₃N₅O₇S₂ 7.19 (d, J =8.4 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.94-6.87 (m, 2H), 6.74 (s, 1H),6.12 (d, J = 5.2 Hz, 1H), 6.08 (d, J = 1.2 Hz, 1H), 5.32 (s, 2H), 4.35(s, 2H), 4.29 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H). ¹H- NMR indicates asingle regioisomer and the structure further confirmed from its nOestudy.  28a 444.3 (M − 1)/ δ 7.27 (s, 1H), 6.67 (s, 1H), 6.52 (s, 1H),445.54 for 5.29 (s, 2H), 3.99 (s, 2H), 3.93 (s, 2H), C₂₁H₂₇N₅O₄S 3.80(s, 3H), 2.94 (d, J = 6.0 Hz, 2H), 1.87-1.78 (m, 3H), 1.65-1.51 (m, 3H),1.27-1.10 (m, 5H), 0.99-0.93 (m, 2H). ¹H- NMR indicates a single-isomerand the structure further confirmed from its nOe study.  28b 444.5 (M −1)/ δ 7.72 (s, 1H), 6.64 (s, 1H), 6.56 (s, 1H), 445.54 for 5.34 (s, 2H),4.15 (s, 4H), 3.80 (s, 3H), C₂₁H₂₇N₅O₄S 2.93 (d, J = 6.0 Hz, 2H),1.90-1.77 (m, 3H), 1.61-1.50 (m, 3H), 1.23-1.07 (m, 5H), 0.99-0.93 (m,2H). ¹H-NMR indicates a single regioisomer and the structure furtherconfirmed from its nOe study.  29a 500.1 (M + 1)/ δ 10.39 (s, 1H), 7.37(d, J = 2.4 Hz, 1H), 499.59 for 7.00-6.95 (m, 1H), 6.80 (d, J = 12.0 Hz,C₂₄H₂₉N₅O₅S 1H), 6.64-6.50 (m, 1H), 6.20 (dt, J = 16.4, 2.4 Hz, 1H),5.73 (dt, J = 10.0, 2.4 Hz, 1H), 5.41 (d, J = 10.8 Hz, 2H), 4.77 (s,1H), 4.65 (s, 1H), 4.47 (s, 1H), 4.43 (s, 1H), 3.91 (s, 3H), 3.36 (d, J= 6.0 Hz, 2H), 1.98-1.93 (m, 1H), 1.86 (d, J = 12.8 Hz, 2H), 1.65 (dd, J= 10.0, 2.8 Hz, 2H), 1.58 (d, J = 12.8 Hz, 1H), 1.27-1.04 (m, 5H).¹H-NMR indicates a single regioisomer and the structure furtherconfirmed from its nOe study.  29b 500.2 (M + 1)/ δ 10.32 (brs, 1H),7.76 (d, J = 5.6 Hz, 1H), 499.59 for 6.86 (s, 1H), 6.74 (s, 1H),6.69-6.61 (m, C₂₄H₂₉N₅O₅S 1H), 6.21 (dt, J = 16.8, 1.6 Hz, 1H), 5.73(dt, J = 10.0, 2.4 Hz, 1H), 5.41 (s, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.45(s, 2H), 3.87 (s, 3H), 3.21 (s, 2H), 1.95-1.82 (m, 3H), 1.58-1.52 (m,3H), 1.29-0.98 (m, 5H). ¹H- NMR indicates a single regioisomer and thestructure further confirmed from its nOe study.  30a 498.05 (M + 1)/ δ10.40 (s, 1H), 7.37 (s, 1H), 7.01 (d, J = 497.57 for 12.0 Hz, 1H), 6.80(s, 1H), 5.43 (d, J = 9.6 C₂₄H₂₇N₅O₅S Hz, 2H), 4.78 (s, 1H), 4.66 (s,1H), 4.58 (d, J = 3.6 Hz, 1H), 4.46 (s, 1H), 4.40 (s, 1H), 3.91 (s, 3H),3.31 (s, 2H), 1.97-1.90 (m, 1H), 1.88 (d, J = 10.0 Hz, 2H), 1.66 (d, J =17.2 Hz, 2H), 1.59 (d, J = 11.6 Hz, 1H), 1.26-1.08 (m, 5H). ¹H-NMRindicates a single regioisomer and the structure further confirmed fromits nOe study.  30b 498.05 (M + 1)/ δ 10.41 (s, 1H), 7.77 (s, 1H), 6.96(s, 1H), 497.57 for 6.82 (s, 1H), 5.44 (s, 2H), 4.72 (s, 2H),C₂₄H₂₇N₅O₅S 4.57 (d, J = 6.4 Hz, 1H), 4.43 (s, 2H), 3.90 (s, 3H), 3.17(d, J = 4.8 Hz, 2H), 1.98-1.92 (m, 1H), 1.86 (d, J = 11.6 Hz, 2H), 1.70-1.56 (m, 3H), 1.25-1.07 (m, 5H). ¹H-NMR indicates a single regioisomerand the structure further confirmed from its nOe study. 31 495.96 (M +1)/ δ 10.21 (brs, 1H), 9.01 (brs, 1H), 7.75 (d, 495.51 for J = 7.2 Hz,1H), 7.70 (s, 1H), 7.51 (brs, C₂₃H₂₁N₅O₆S 1H), 7.34 (s, 1H), 7.18-6.92(m, 3H), 6.82- 6.61 (m, 2H), 5.32 (s, 2H), 4.08 (s, 2H), 3.79 (s, 3H),3.72 (s, 3H). 32 534.0 (M + 1)/ δ 10.15 (brs, 1H), 7.80-7.77 (m, 2H),7.58 533.57 for (t, J = 6.0 Hz, 2H), 7.41 (s, 1H), 7.18 (d, C₂₂H₂₃N₅O₇S₂J = 7.6 Hz, 1H), 7.07-7.08 (m, 1H), 6.82 (2, 1H), 6.74 (s, 1H), 6.65 (q,J = 10.0, 10.0 Hz, 1H), 6.02 (d, J = 16.4 Hz, 1H), 5.91 (d, J = 10.0 Hz,1H), 5.38 (s, 2H), 3.91 (d, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.77 (2, 3H).33 563.89 (M + 1)/ δ 7.74 (s, 1H), 7.40 (s, 1H), 7.18 (t, J = 563.60 for8.4 Hz, 2H), 6.63-6.50(m, 5H), 6.04-5.97 C₂₃H₂₅N₅O₈S₂ (m, 5H), 5.89 (d,J = 10.0 Hz, 1H), 5.30 (s, 2H), 3.91 (s, 2H), 3.83 (s, 3H), 3.55 (s,3H). 34 525.93 (M + 1)/ δ 9.53 (s, 1H), 9.03 (t, J = 5.2 Hz, 1H), 525.54for 7.75 (s, 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.38 C₂₄H₂₃N₅O₇S (s, 1H),6.83 (s, 1H), 6.75 (d, J = 8.4 Hz, 3H), 5.37 (s, 2H), 4.13 (s, 2H), 4.10(d, J = 4.0 Hz, 1H), 3.87 (s, 3H), 3.74 (s, 6H, merged). 35 496.20 (M +1)/ δ 10.92 (s, 1H), 9.06-9.00 (m, 1H), 7.72 495.51 for (s, 1H),7.48-7.41 (m, 2H), 7.37 (s, 1H), C₂₃H₂₁N₅O₆S 7.22-6.95 (m, 2H), 6.76 (s,1H), 6.65 (s, 1H), 5.34 (s, 2H), 4.11 (dd, J = 10.0, 5.6 Hz, 3H), 3.84(s, 3H), 3.77 (s, 3H). 36 524.3 (M + 1)/ δ 10.38 (br s, 1H), 9.03 (brs,1H), 8.03 (br 523.52 for s, 1H), 7.80-7.73 (m, 4H), 7.37 (s, 1H),C₂₄H₂₁N₅O₇S 6.86 (s, 1H), 6.72 (s, 1H), 5.36 (s, 2H), 4.12 (s, 1H), 4.10(s, 2H), 3.80 (s, 3H), 3.78 (s, 3H). 37 510.0 (M + 1)/ δ 9.02 (t, J =7.2 Hz, 1H), 8.05 (dd, J = 509.49 for 7.2, 2.0 Hz, 1H), 7.80 (dd, J =6.4, 2.0 Hz, C₂₃H₁₉N₅O₇S 1H), 7.74-7.71 (m, 3H), 7.37 (s, 1H), 6.87 (s,1H), 6.72 (s, 1H), 5.36 (s, 2H), 4.12 (s, 1H), 4.10 (s, 2H), 3.84 (s,3H); ¹H-NMR didn't show 2 exchangeable protons. 38 524.2 (M + 1)/ δ 9.03(t, J = 5.6 Hz, 1H), 8.13-7.98 (m, 523.52 for 4H), 7.71 (s, 1H), 7.36(s, 1H), 7.39 (d, J = C₂₄H₂₁N₅O₇S 12.0 Hz, 1H), 6.71 (s, 1H), 6.62 (s,1H), 5.33 (s, 2H), 4.11 (d, J = 5.6 Hz, 1H), 4.09 (s, 2H), 3.86 (s, 3H),3.82 (s, 3H). 39 459.95 (M + 1)/ δ 8.49 (t, J = 5.6 Hz, 1H), 8.39 (t, J= 5.6 459.45 for Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.61 (d,C₂₁H₁₈FN₃O₆S J = 8.0 Hz, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.45 (s, 1H),7.27-7.15 (m, 4H), 6.33-6.26 (m, 1H), 6.12 (d, J = 15.2 Hz, 1H), 5.61(dd, J = 10.0, 2.0 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 3.83 (d, J = 6.0Hz, 2H), 3.16 (s, 1H). 40 500.04 (M + 1)/ δ 8.59 (q, J = 6.0 Hz, 1H),7.84-7.80 (m, 499.51 for 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.48-7.42C₂₄H₂₂FN₃O₆S (m, 2H), 7.24-6.96 (m, 5H), 6.61-6.52 (m, 1H), 6.13 (dt, J= 13.2, 2.4 Hz, 1H), 5.65 (dd, J = 10.0, 2.4 Hz, 1H), 4.44-4.32 (m, 2H),3.80-3.46 (m, 4H), 3.13-2.95 (m, 1H), 2.18-1.89 (m, 2H). 41 523.15 (M +1)/ δ 10.78 (d, J = 2.0 Hz, 1H), 10.29 (d, J = 522.60 for 2.4 Hz, 1H),8.57 (d, J = 4.8 Hz, 1H), 8.20 C₂₇H₂₇FN₄O₄S (s, 1H), 8.10 (s, 1H), 7.87(s, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.69 (q, J = 5.6 Hz, 1H), 7.55 (s,1H), 7.39 (t, J = 9.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 2H), 6.89-6.82 (m,1H), 6.12 (dd, J = 16.4, 2.4 Hz, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H),4.64 (d, J = 12.0 Hz, 1H), 4.23 (d, J = 13.2 Hz, 1H), 3.18 (t, J = 11.2Hz, 1H), 2.93 (t, J = 12.0 Hz, 1H), 2.73 (t, J = 12.0 Hz, 1H), 2.40 (s,3H), 1.91 (d, J = 13.2 Hz, 2H), 1.64 (t, J = 12.0 Hz, 2H). 42 559.0 (M +1)/ δ 10.78 (d, J = 2.4 Hz, 1H), 10.29 (d, J = 558.64 for 2.4 Hz, 1H),8.59 (d, J = 5.2 Hz, 1H), 8.20 C₂₆H₂₇FN₄O₅S₂ (s, 1H), 8.11 (s, 1H), 7.90(s, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.68 (q, J = 6.8 Hz, 1H), 7.57 (s,1H), 7.39 (t, J = 10.0 Hz, 1H), 7.34-7.28 (m, 2H), 6.90-6.83 (m, 1H),6.21-6.12 (m, 2H), 3.71 (d, J = 11.6 Hz, 2H), 2.81-2.65 (m, 3H), 2.41(s, 3H), 1.95 (d, J = 10.8 Hz, 2H), 1.86-1.75 (m, 2H). 43 522.4 (M + 1)/δ 10.08 (br s, 1H), 9.04 (br s, 1H), 7.78 (d, 521.55 for J = 7.2 Hz,1H), 7.75 (s, 1H), 7.62 (t, J = C₂₅H₂₃N₅O₆S 7.6 Hz, 1H), 7.39 (s, 1H),7.17 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.92 (s, 2H), 5.41(s, 2H), 4.12 (d, J = 8.4 Hz, 3H), 3.87 (br s, 1H), 3.66 (s, 3H), 0.78(d, J = 6.0 Hz, 2H), 0.63 (s, 2H). 44 511.5(M + 1)/ δ 10.21 (s, 1H),7.80 (d, J = 8.0 Hz, 1H), 510.16 for 7.62 (t, J = 7.6 Hz, 1H), 7.18 (d,J = 8.4 C₂₅H₂₆N₄O₆S Hz, 1H), 7.09 (t, J = 7.6 Hz, 2H), 6.78 (s, 1H),3.76-3.78 (m, 6H), 3.58 (d, J = 10.4 Hz, 2H), 3.40-3.39 (m, 3H), 2.82(s, 2H), 2.64-2.56 (m, 2H), 1.46-1.50 (m, 2H) 0.92-0.90 (m, 2H). 45510.1(M + 1)/ δ 10.08 (s, 1H), 7.86 (s, 1H), 7.79-7.77 509.14 for (m,1H), 7.59-7.60 (m, 1H), 7.17 (d, J = C₂₄H₂₃N₅O₆S 8.4 Hz, 1H), 7.60-7.04(m, 1H), 6.85 (s, 1H), 6.68 (s, 1H), 5.38 (d, J = 8.4 Hz, 2H), 4.58 (s,2H), 4.50 (s, 1H), 4.32 (s, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.05 (s,3H). 46 553.1(M + 1)/ δ 10.45 (s, 1H), 9.05 (t, J = 5.2 Hz, 1H), 552.14for 8.62 (d, J = 3.2 Hz, 1H), 7.86 (d, J = 8.0 C₂₅H₂₄N₆O₇S Hz, 1H), 7.74(s, 1H), 7.53 (s, 1H), 7.49 (d,J = 8.0 Hz, 1H), 7.38 (s, 1H), 6.86 (s,1H), 6.74 (s, 1H), 5.37 (s, 2H), 4.12 (d, J = 5.6 Hz, 3H), 3.83 (s, 3H),3.79 (s, 3H) 2.79 (d, J = 4.4 Hz, 3H), 47 512.1(M + 1)/ δ 10.15 (s, 1H),7.82-7.78 (m, 2H), 7.64- 511.15 for 7.60 (m, 1H), 7.42 (d, J = 4.8 Hz,1H), C₂₄H₂₅N₅O₆S 7.20 (d, J = 8.0 Hz, 1H), 7.11-7.07 (m, 1H), 6.91-6.84(m, 1H), 6.76-6.69 (m, 1H), 6.14 (dd, J = 2.4, 2.4 Hz, 2H),5.68- 5.63(m, 1H), 5.39 (d, J = 4.0 Hz, 2H), 4.36 (s, 2H), 3.80 (s, 3H), 3.77 (s,3H), 2.97-2.86 (s, 3H). 48 485.1(M + 1)/ δ 8.92 (d, J = 6.8 Hz, 1H),8.25 (s, 1H), 484.14 for 7.78 (d, J = 7.2 Hz, 1H), 7.31-7.25 (m,C₂₃H₂₄N₄O₆S 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H),6.79 (s, 1H), 6.54 (s, 1H), 4.16 (s, 1H), 4.08 (s, 1H), 3.84 (s, 3H),3.71 (s, 3H), 3.63-3.60 (m, 2H), 2.66 (s, 1H), 2.32 (s, 2H), 2.06-2.63(m, 2H), 1.35- 1.25 (m, 1H), 49 501.4(M + 1)/ δ 9.99 (brs, 1H), 8.03 (d,J = 7.2 Hz, 1H), 500.17for 7.82 (dd, J = 8.0, 8.0 Hz, 1H), 7.63 (t, J =C₂₄H₂₈N₄O₆S 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 7.6 Hz,2H), 6.79 (s, 1H), 6.23-6.16 (m, 1H), 6.08 (dd, J = 16.8, 17.2 Hz, 1H),5.58 (dd, J = 10.0, 10.0 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.71-3.66(m, 3H), 2.95- 2.87 (m, 2H), 2.27-2.15 (m, 2H), 1.80- 1.77 (m, 2H),1.49-1.45 (m, 2H). 50 513.2 (M + 1)/ δ 10.04 (s, 1H), 7.81 (d, J = 8.0Hz, 1H), 512.17 for 7.56 (t, J = 6.4 Hz, 1H), 7.16 (d, J = 8.8C₂₅H₂₈N₄O₆S Hz, 1H), 7.08 (t, J = 8.0 Hz, 2H), 6.72 (s, 1H), 6.63-6.50(m, 1H), 6.13 (dd, J = 16.4, 16.8 Hz, 1H), 5.66 (dd, J = 10.8, 10.4 Hz,1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.74-3.71 (m, 1H), 3.65 (s, 2H),3.60-3.37 (m, 5H), 2.85-2.76 (m, 2H), 2.25-2.54 (m, 2H). 51 498.5 (M +1)/ δ 10.13 (s, 1H), 8.35-8.30 (m, 1H), 7.77 497.14 for (d, J = 7.2 Hz,2H), 7.38 (s, 2H), 7.01-6.94 C₂₃H₂₃N₅O₆S (m, 2H), 6.61-6.59 (m, 2H),6.24-6.17 (m, 1H), 6.10 (dd, J = 16.8, 16.8 Hz, 1H), 5.58 (dd, J = 10.0,10.0 Hz, 1H), 5.32 (s, 2H), 4.17 (d, J = 5.2 Hz, 2H), 3.82 (s, 3H), 3.73(s, 3H). 52 523.47 (M + 1)/ δ 11.09 (broad s, 1H), 9.06 (t, J = 5.6 Hz,522.54 for 1H), 8.68 (s, 1H), 8.41 (s, 1H), 8.07 (d, J = C₂₄H₂₂N₆O₆S 7.6Hz, 2H), 7.73 (s, 2H), 7.37 (s, 1H), 6.82 (s, 1H), 6.71 (s, 1H), 5.36(s, 2H), 4.12 (t, J = 3.2 Hz, 3H), 3.84 (s, 3H), 2.79 (d, J = 4.4 Hz,3H). 53 526.5(M + 1)/ δ 10.11 (s, 1H), 8.90 (m, 1H), 7.79 (d, J = 525.54for 7.6 Hz, 1H), 7.71 (s, 1H), 7.60 (t, J = 8.0 C24H23N5O7S Hz, 1H),7.35 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.84(s, 1H), 6.72 (s, 1H), 5.35 (s, 2H), 4.17 (s, 2H), 4.10 (d, J = 5.6 Hz,2H), 3.80 (s, 3H), 3.76 (s, 3H). —OH proton not observed 54 542.38(M +1)/ δ 10.15 (s, 1H), 8.32 (t, J = 5.6 Hz, 1H), 541.58 for 7.81 (dd, J =8.0, 8.0 Hz, 1H), 7.73 (s, C25H27N5O7S 1H), 7.64-7.60 (m, 1H), 7.38 (s,1H), 7.20 (d, J = 8.4 Hz, 1H), 7.11-7.07 (m, 1H), 6.86 (s, 1H), 6.75 (s,1H), 6.63-6.58 (m, 1H), 6.10-6.05 (m, 1H), 5.37 (s, 2H), 4.16 (d, J =5.6 Hz, 2H), 4.01 (dd, J = 4.4, 4.4 Hz, 2H), 3.83 (s, 3H), 3.79 (s, 3H),3.26 (s, 3H). 55 506.1 (M + 1)/ δ 10.78 (s, 1H), 10.15(s, 1H), 9.38 (t,J = 505.55 for 6.0 Hz, 1H), 8.66 (d, J = 4.0 Hz, 1H), 8.62 C25H23N5O5S(d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 8.07-8.04 (m, 2H), 7.98(d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.55 (s,1H), 7.24 (d, J = 4.8 Hz, 1H), 4.42 (d, J = 6.0 Hz, 2H), 4.24 (s, 1H),2.76 (d, J = 4.4 Hz, 3H), 2.41 (s, 3H). 56 579.4(M + 1)/ δ 9.57 (s, 1H),7.50-7.53 (m, 1H), 7.43 (s, 578.64for 1H), 7.31-7.25 (m, 1H), 7.28 (s,1H), 7.15 C29H30N4O7S (d, J = 4.0 Hz, 1H), 7.05 (s, 2H), 7.01-6.90 (m,1H), 6.80 (d, J = 8.4 Hz, 2H), 6.15- 6.12 (m, 1H), 5.71-5.69 (m, 1H),4.02 (s, 3H), 3.79 (s, 6H), 3.71-3.70 (m, 4H), 3.25 (s, 4H). 57510.1(M + 1)/ δ 10.14 (s, 1H), 8.80 (t, J = 5.2 Hz, 1H), 509.54 for 7.80(d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.61 C24H23N5O6S (s, 1H), 7.36 (s,1H), 7.17 (s, 1H), 7.08 (s, 1H), 6.84 (s, 1H), 6.73 (s, 1H), 5.36 (s,2H), 4.09 (d, J = 6.0 Hz, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 1.92 (s, 3H).58 579.1(M + 1)/ δ 9.61 (s, 1H), 7.49-7.47(m, 1H), 7.37- 578.64 for 7.32(m, 3H), 7.17-7.10 (m, 3H), 6.79- C29H30N4O7S 6.70 (m, 3H), 6.11 (dd, J= 16.4, 16.4 Hz, 1H), 5.66 (dd, J = 10.0, 10.0 Hz, 1H), 3.95 (s, 3H),3.77 (s, 6H), 3.44-3.32 (m, 4H), 2.78-2.32 (m, 4H). 59 548.97(M + 1)/¹H-NMR (400 MHz, CD₃OD) δ7.97 (dd, 548.63 for J = 7.2, 7.6 Hz, 1H),7.58-7.54 (m, 1H), C₂₄H₂₈N₄O₇S₂ 7.12-7.05 (m, 2H), 6.99 (s, 1H), 6.82(s, 1H), 6.75-6.66 (m, 1H), 6.21-6.17 (m, 2H), 3.98 (s, 3H), 3.84 (s,3H), 3.69 (s, 2H), 3.30 (m, 2H merged in solvent peak), 3.09-3.06 (m,2H), 2.87-2.86 (m, 2H), 2.75-2.70 (m, 2H), 2.44 (dd, J = 9.6, 9.2 Hz,2H). 60 553.1(M + 1)/ δ 10.20 (s, 1H), 8.90 (t, J = 5.6 Hz, 1H), 552.56for 8.22 (t, J = 5.6 Hz, 1H), 7.79 (t, J = 6.4 C25H24N6O7S Hz, 1H), 7.70(s, 1H), 7.54 (brs, 1H), 7.37 (s, 1H), 7.12 (d, J = 10.8 Hz, 2H), 6.79(t, J = 8.0 Hz, 2H), 5.34 (s, 2H), 4.16 (s, 1H), 4.10 (d, J = 5.6 Hz,2H), 3.82 (s, 3H), 3.75 (s, 3H), 3.68 (d, J = 6.4 Hz, 2H). 61 555.1(M +1)/ δ 10.14 (s, 1H), 8.33 (t, J = 5.6 Hz, 1H), 554.58 for 8.22 (t, J =5.6 Hz, 1H), 7.79 (t, J = 7.2 C25H26N6O7S Hz, 1H), 7.21 (s, 1H), 7.61(brs, 1H), 7.37 (s, 1H), 7.17 (d, J = 6.4 Hz, 2H), 6.85-6.73 (m, 2H),6.32-6.25 (m, 1H), 6.10 (dd, J = 16.8, 17.2 Hz, 1H), 6.60 (dd, J = 10.0,10.4 Hz, 1H), 5.35 (s, 2H), 4.11(d, J = 5.6 Hz, 2H), 3.82 (s, 3H), 3.77(t, J = 6.8 Hz, 5H). 62 496.90(M + 1)/ δ 8.80 (t, J = 5.2 Hz, 1H), 8.29(s, 1H), 496.50 for 7.90 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.37C22H20N6O6S (t, J = 7.6 Hz, 1H), 7.19 (brs, 1H), 6.99 (d, J = 8.0 Hz,1H), 6.93 (t, J = 7.2 Hz, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 5.39 (s, 2H),4.23 (d, J = 5.2 Hz, 2H), 3.83 (s, 3H), 3.71 (s, 3H). 63 514.4(M + 1)/ δ8.51 (s, 1H), 8.13 (s, 1H), 7.80 (d, J = 513.57 for 7.2 Hz, 1H), 7.52(brs, 1H), 7.13 (d, J = C24H27N5O6S 8.0 Hz, 1H), 7.02-6.98 (m, 2H), 6.71(s, 1H), 4.09 (d, J = 4.8 Hz, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 3.57 (s,2H), 2.85 (d, J = 9.2 Hz, 2H), 2.16 (brs, 1H), 2.01-2.05 (m, 2H),1.65-1.58 (m, 4H). 64 499.2 (M + 1)/ 10.01(brs, 1H), 8.67 (s, 1H), 7.80(s, 1H), 498.55 for 7.61 (s, 1H), 7.19 (d, J = 7.2 Hz, 3H), 6.79C24H26N4O6S (s, 1H), 4.10 (s, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.65(brs, 2H), 2.89 (s, 3H), 2.65- 2.49 (m, 2H), 1.78-1.73 (m, 2H), 1.49-1.51 (m, 2H), 65 540.2 (M + 1)/ 10.54 (brs, 1H), 9.02 (s, 1H), 7.91 (d,J = 539.52 for 8.0 Hz, 1H), 7.73 (s, 1H), 7.60 (s, 2H), C24H21N5O8S 7.37(s, 1H), 6.84 (s, 1H), 6.71 (s, 1H), 5.36 (s, 2H), 4.12 (t, J = 5.6 Hz,2H), 3.83 (s, 3H), 3.79 (s, 3H), 2.95 (brs, 1H) Acid proton notobserved. 66 496.4 (M + 1)/ 9.05 (brs, 1H), 7.83 (d, J = 7.2 Hz, 1H),495.51 for 7.72 (s, 1H), 7.39 (s, 1H), 7.34 (t, J = 8.0 C22H21N7O5S Hz,1H), 6.94-6.87 (m, 2H), 6.47 (s, 1H), 6.64 (s, 1H), 5.15 (s, 2H), 4.14(d, J = 5.6 Hz, 2H), 3.72 (s, 3H), 3.56 (s, 3H) Exchangeable proton—NH—NH not observed. 67 500.25 (M + 1)/ 10.05 (brs, 1H), 8.51 (s, 1H),7.82 (q, J = 499.54 for 8.0, 7.6 Hz, 1H), 7.55 (brs, 1H), 7.15 (d,C23H25N5O6S J = 8.0 Hz, 1H), 7.05 (d, J = 6.8 Hz, 2H), 6.75 (s, 1H),4.11 (d, J = 5.6 Hz, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 3.70 (s, 2H), 2.91(t, J = 8.4 Hz, 1H) 2.82 (t, J = 7.6 Hz, 1H), 2.50-2.49 (s, 3H), 1.96(q, J = 14.0, 14.0 Hz, 2H). 68 523.1 (M + 1)/ 9.90 (brs, 1H), 8.98 (s,1H), 7.92 (brs, 522.54 for 1H), 7.67 (s, 2H), 7.55-7.92 (m, 5H), 6.51-C24H22N6O6S 6.52 (m, 1H), 5.29 (s, 2H), 4.09 (t, J = 5.2 3H), 3.81(s,3H) 2.76 (s, 2H). 69 524.3 (M + 1)/ 10.05 (s, 1H), 9.06 (t, J = 5.6 Hz,1H), 523.56 for 7.74 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.46 C25H25N5O6S(d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.86 (s,1H), 6.74 (s, 1H) 5.37 (s, 2H), 7.12 (t, J = 1.6 Hz, 3H), 3.81 (s, 3H),3.73 (s, 3H), 2.62 (q, J = 15.2, J = 15.2 Hz, 2H) 1.23 (t, J = 9.2 Hz,3H) 70 673.76 (M + H)/ 10.15 (brs, 1H), 9.01 (s, 1H), 7.80 (d, J =673.59 for 6.4 Hz, 1H), 7.71 (s, 1H), 7.59 (brs, 1H), C26H20F5N5O7S27.31 (s, 1H), 7.16-7.12 (m, 2H), 6.74 (brs, 2H), 5.31 (s, 2H), 4.10 (d,J = 2.4 Hz, 2H), 3.84 (s, 3H), 3.77 (s, 3H). 71 577.3 (M + 1)/ 9.60 (s,1H), 7.53 (t, J = 8.8 Hz, 1H), 7.44 576.62 for (s, 1H), 7.29 (s, 1H),7.22 (d, J = 5.6 Hz, C29H28N4O7S 1H), 7.04 (s, 1H), 7.03 (d, J = 2.0 Hz,2H), 6.80 (s, 1H), 6.78 (s, 1H), 4.61 (s, 1H), 4.02 (s, 3H), 3.85 (t, J= 4.8 Hz, 2H), 3.79 (s, 6H), 3.66 (t, J = 4.8 Hz, 2H), 3.29 (t, J = 9.6Hz, 2H), 3.26 (t, J = 5.2 Hz, 2H). 72 615.2(M + 1)/ δ 9.59 (s, 1H), 7.51(t, J = 8.5 Hz, 1H), 614.69 for 7.43 (s, 1H), 7.38-7.31 (m, 1H), 7.28(s, C28H30N4O8S2 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.06-6.98 (m, 2H), 6.88(dd, J = 10.0, 16.5 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 6.24-6.17 (m,2H), 4.02 (s, 3H), 3.79 (s, 6H), 3.38-3.32 (m, 4H), 3.24-3.15 (m, 4H).73 600.14(M + 1)/ δ 9.60 (br d, J = 2.1 Hz, 1H), 7.51 (t, J = 601.07 for8.5 Hz, 2H), 7.44 (s, 1H), 7.38-7.31 (m, C28H29ClN4O7S 1H), 7.29 (s,1H), 7.21 (d, J = 7.6 Hz, 1H), 7.08-7.00 (m, 1H), 6.79 (d, J = 8.5 Hz,2H), 4.45 (s, 2H), 4.02 (s, 3H), 3.81-3.77 (m, 6H), 3.67-3.60 (m, 4H),3.25 (br d, J = 5.0 Hz, 2H), 2.54 (s, 2H). 74 546.16(M + 1)/ δ10.20-10.07 (m, 1H), 7.83 (dd, J = 1.6, 546.60 for 7.8 Hz, 1H),7.72-7.59 (m, 1H), 7.46-7.39 C28H26N4O6S (m, 1H), 7.38-7.32 (m, 2H),7.28 (s, 1H), 7.21 (br d, J = 8.0 Hz, 2H), 7.13-7.01 (m, 1H), 6.52-6.51(m, 1H), 4.61 (s, 1H), 4.16- 4.11 (m, 1H), 3.97 (s, 1H), 3.87-3.82 (m,3H), 3.81 (s, 3H), 3.68-3.63 (m, 2H), 3.30 (br s, 2H), 3.27-3.22 (m,2H). 75 564.2(M + 1)/ δ 8.97-8.91 (m, 1H), 8.16 (br s, 1H), 7.54- 563.63for 7.47 (m, 1H), 7.36-7.31 (m, 1H), 6.79 (dd, C29H29N3O7S J = 2.3, 8.6Hz, 1H), 6.55-6.51 (m, 1H), 6.50-6.42 (m, 2H), 6.18-6.14 (m, 1H),6.13-6.09 (m, 1H), 5.75 (br d, J = 1.1 Hz, 1H), 5.70 (d, J = 2.2 Hz,1H), 5.67 (d, J = 2.3 Hz, 1H), 5.66-5.64 (m, 1H), 5.63 (d, J = 2.3 Hz,1H), 4.45 (br d, J = 1.6 Hz, 1H), 4.40 (br d, J = 2.2 Hz, 2H), 4.16 (brd, J = 2.9 Hz, 2H), 3.82-3.80 (m, 9H). 76 495.0(M + 1)/ δ 12.51 (br d, J= 5.6 Hz, 1H), 9.30-9.13 494.53 for (m, 1H), 9.11-8.96 (m, 1H),8.37-8.33 (m, C23H22N6O5S 1H), 7.72-7.65 (m, 2H), 7.60-7.52 (m, 1H),7.36 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.05-6.97 (m,1H), 6.68 (s, 1H),5.32-5.29 (m, 2H), 4.13-4.09 (m, 3H), 3.80 (s, 3H), 3.72 (s, 3H). 77537.3(M + 1)/ δ 10.18-9.92 (m, 1H), 7.81 (dd, J = 1.6, 536.62 for 7.9Hz, 1H), 7.57 (br t, J = 7.6 Hz, 1H), C23H28N4O7S2 7.34 (d, J = 7.1 Hz,1H), 7.16 (br d, J = 8.4 Hz, 1H), 7.06 (br t, J = 7.7 Hz, 1H), 7.01 (s,1H), 6.77-6.66 (m, 1H), 6.01 (d, J = 16.4 Hz, 1H), 5.91 (d, J = 10.0 Hz,1H), 3.87-3.82 (m, 3H), 3.80-3.75 (m, 4H), 3.60-3.55 (m, 2H), 3.04-2.95(m, 1H), 2.83-2.71 (m, 2H), 2.05 (br d, J = 7.1 Hz, 2H), 1.79-1.71 (m,2H), 1.55- 1.40 (m, 2H). 78 602.2(M + 1)/ δ 10.15 (s, 1H), 7.93 (t, J =5.9 Hz, 1H), 601.62 for 7.85-7.77 (m, 3H), 7.67-7.58 (m, 2H),C26H24FN5O7S2 7.41-7.32 (m, 2H), 7.25 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H),7.13-7.07 (m, 1H), 6.79- 6.71 (m, 2H), 5.33 (s, 2H), 3.85 (br d, J = 5.9Hz, 3H), 3.83 (s, 2H), 3.79 (s, 3H). 79 584.5(M + 1)/ δ 10.13 (br s,1H), 7.89 (br t, J = 5.9 Hz, 583.63 for 1H), 7.82-7.73 (m, 3H),7.63-7.47 (m, C26H25N5O7S2 5H), 7.23 (s, 1H), 7.21-7.01 (m, 1H), 6.74(br d, J = 17.6 Hz, 1H), 5.31 (s, 2H), 3.92- 3.81 (m, 3H), 3.78 (s, 2H),3.41-3.33 (m, 3H) —NH protons not observed. 80 636.0(M − 1)/ δ 10.12 (s,1H), 8.21-8.12 (m, 1H), 7.80 637.61 for (dd, J = 1.6, 7.8 Hz, 1H),7.71-7.55 (m, C26H22F3N5O7S2 4H), 7.29 (s, 1H), 7.19 (br d, J = 7.9 Hz,1H), 7.13-7.04 (m, 1H), 6.83-6.69 (m, 2H), 5.33 (s, 2H), 3.93 (d, J =5.8 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H). 81 562.2(M + 1)/ δ 7.96-7.67(m, 1H), 7.62 (s, 1H), 7.56 (br 561.63 for t, J = 5.4 Hz, 1H), 7.48-7.38(m, 1H), C24H27N5O7S2 7.07-6.97 (m, 1H), 6.70-6.55 (m, 2H), 6.53-6.45(m, 1H), 6.04 (br s, 1H), 5.85 (br s, 1H), 5.40-5.32 (m, 2H), 3.94-3.89(m, 4H), 3.84-3.81 (m, 2H), 3.75-3.68 (m, 3H), 3.22-3.15 (m, 3H),1.19-1.09 (m, 3H). 82 686.5(M + 1)/ δ 10.03 (s, 1H), 7.69 (d, J = 6.6Hz, 1H), 685.60 for 7.62 (d, J = 1.5 Hz, 1H), 7.45 (br d, J =C27H20F5N5O7S2 7.8 Hz, 2H), 7.11 (br d, J = 8.4 Hz, 1H), 6.91 (br d, J =5.6 Hz, 1H), 6.80 (br s, 1H), 5.34 (s, 2H), 4.75 (s, 1H), 4.62 (s, 1H),4.57 (s, 1H), 4.52 (s, 1H), 3.84 (s, 3H), 3.77-3.74 (m, 3H). 83619.2(M + 1)/ δ 10.13 (s, 1H), 8.71 (d, J = 2.1 Hz, 1H), 618.08 for 8.24(t, J = 5.8 Hz, 1H), 8.11 (dd, J = 2.5, C25H23ClN6O7S2 8.4 Hz, 1H), 7.80(dd, J = 1.6, 7.9 Hz, 1H), 7.68-7.58 (m, 3H), 7.26 (s, 1H), 7.20 (d, J =8.1 Hz, 1H), 7.09 (t, J = 7.3 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 5.32(s, 2H), 3.95 (d, J = 5.8 Hz, 2H), 3.83 (s, 3H), 3.79 (s, 3H). 84619.1(M + 1)/ δ 10.17-10.07 (m, 1H), 8.71 (d, J = 2.1 Hz, 618.08 for1H), 8.24 (t, J = 5.8 Hz, 1H), 8.11 (dd, J = C25H23ClN6O7S21 2.6, 8.4Hz, 1H), 7.80 (dd, J = 1.5, 7.8 Hz, 1H), 7.70-7.55 (m, 3H), 7.26 (s,1H), 7.20- 7.13 (m, 1H), 7.11-7.04 (m, 1H), 6.82- 6.71 (m, 2H), 5.31 (s,2H), 3.95 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H). 85 553.5(M +1)/ δ 9.19-8.85 (m, 1H), 8.57-8.22 (m, 1H), 552.56 for 8.06-7.80 (m,1H), 7.77-7.67 (m, 1H), C25H24N6O7S 7.33 (br s, 3H), 7.23-6.99 (m, 2H),5.28 (br s, 3H), 4.15-4.05 (m, 2H), 3.86-3.71 (m, 3H), 3.19-3.13 (m,3H), 2.75 (br d, J = 3.4 Hz, 3H). amine proton not observed. 86540.5(M + 1)/ δ 10.73-10.47 (m, 1H), 9.04 (br t, J = 5.3 539.52 for Hz,1H), 8.44-8.31 (m, 1H), 8.22-8.08 (m, C24H21N5O8S 1H), 7.82-7.69 (m,1H), 7.40-7.25 (m, 2H), 6.98-6.65 (m, 2H), 5.52 (s, 3H), 4.23- 3.96 (m,2H), 3.83-3.67 (m, 6H). carboxylic acid proton not observed. 87562.6(M + 1)/ δ 13.11-12.97 (m, 1H), 8.96 (br s, 1H), 561.61 for 8.16(br s, 1H), 7.82-7.74 (m, 1H), 7.71- C29H27N3O7S 7.65 (m, 1H), 7.59-7.52(m, 1H), 7.50 (s, 1H), 7.50-7.46 (m, 1H), 6.80 (d, J = 8.5 Hz, 1H),6.61-6.58 (m, 1H), 4.87 (br s, 1H), 4.63-4.56 (m, 4H), 4.40-4.28 (m,1H), 3.98-3.96 (m, 3H), 3.85-3.81 (m, 6H), 3.77 (br d, J = 11.1 Hz, 2H).88 488.3(M + 1)/ δ 10.15-9.88 (m, 1H), 8.85 (br t, J = 5.6 487.53 forHz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.47 (br C23H25N3O7S d, J = 7.9 Hz,1H), 7.14-7.07 (m, 2H), 6.78 (s, 1H), 4.57 (s, 2H), 4.13 (s, 1H), 3.86(s, 3H), 3.74 (s, 3H), 3.51-3.42 (m, 2H), 3.32 (s, 2H), 2.61 (q, J = 7.5Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H). 89 502.1(M + 1)/ δ 9.97 (s, 1H),8.85-8.61 (m, 1H), 7.64 (d, 501.16 for J = 2.2 Hz, 1H), 7.47 (dd, J =2.0, 8.4 Hz, C24H27N3O7S 1H), 7.15-7.07 (m, 2H), 6.77 (s, 1H), 4.54 (s,2H), 4.09 (s, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 3.51-3.44 (m, 2H),3.22-3.10 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.80-1.63 (m, 2H), 1.15 (t,J = 7.6 Hz, 3H). 90 540.1(M + 1)/ δ 10.06 (s, 1H), 7.64 (d, J = 2.3 Hz,1H), 539.14 for 7.51-7.41 (m, 1H), 7.24 (t, J = 5.7 Hz, C23H29N3O8S21H), 7.09 (br s, 1H), 6.80-6.57 (m, 2H), 6.05-5.90 (m, 3H), 4.54 (s,2H), 3.86 (s, 3H), 3.74 (s, 3H), 3.54-3.44 (m, 2H), 2.96- 2.87 (m, 2H),2.60 (q, J = 7.4 Hz, 2H), 1.73 (quin, J = 6.6 Hz, 2H), 1.15 (t, J = 7.6Hz, 3H). 91 457.3 (M + 1)/ δ 10.57-10.42 (m, 1H), 9.14 (t, J = 5.6 Hz,456.45 for 1H), 8.64 (s, 1H), 8.23-8.19 (m, 1H), 8.04 C20H17FN6O4S (d, J= 1.9 Hz, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.82-7.78 (m, 1H), 7.76 (s,1H), 7.67- 7.60 (m, 1H), 7.41-7.32 (m, 1H), 7.29- 7.20 (m, 1H),4.29-4.19 (m, 2H), 4.16 (s, 1H), 2.50 (td, J = 1.8, 3.6 Hz, 3H). 92507.4(M + 1)/ δ 10.91-10.69 (m, 1H), 10.42 (brs, 1H), 506.14 for 8.61(dd, J = 2.3, 4.9 Hz, 1H), 8.29-8.18 C26H23FN4O4S (m, 1H), 8.11 (s, 1H),7.94 (d, J = 13.5 Hz, 1H), 7.81 (br t, J = 7.5 Hz, 1H), 7.70-7.61 (m,1H), 7.57 (s, 1H), 7.45-7.23 (m, 3H), 4.52 (s, 1H), 3.96 (dd, J = 7.9,11.8 Hz, 1H), 3.92-3.85 (m, 1H), 3.71-3.61 (m, 1H), 3.59-3.49 (m, 1H),3.44-3.35 (m, 1H), 2.54 (br d, J = 3.1 Hz, 1H), 2.41 (s, 3H), 2.22-2.07(m, 1H). 93 617.1(M − 1)/ δ 8.19 (br t, J = 5.3 Hz, 1H), 7.71 (s, 1H),618.16 for 7.62 (d, J = 2.1 Hz, 1H), 7.58-7.53 (m, C26H30N6O8S2 1H),7.43-7.35 (m, 2H), 7.14-7.05 (m, 1H), 6.88-6.71 (m, 2H), 6.70-6.64 (m,1H), 5.99 (d, J = 16.6 Hz, 1H), 5.89 (d, J = 10.0 Hz, 1H), 5.36 (s, 2H),4.11 (d, J = 5.6 Hz, 2H), 3.82 (s, 3H), 3.74 (s, 3H), 3.48 (d, J = 6.1Hz, 2H), 2.59 (br d, J = 7.6 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H). amineproton not observed. 94 581.1(M + 1)/ δ 10.27-10.02 (m, 1H), 8.77 (br t,J = 4.9 580.17 for Hz, 1H), 8.25 (s, 1H), 8.21-8.12 (m, 1H), C27H28N6O7S7.88 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.49-7.34 (m, 1H), 7.08 (td, J =2.3, 4.8 Hz, 1H), 6.96-6.88 (m, 1H), 6.75 (br d, J = 11.0 Hz, 1H), 5.43(s, 2H), 4.12 (s, 1H), 3.84 (s, 6H), 3.25-3.13 (m, 4H), 2.64-2.56 (m,2H), 1.14 (t, J = 7.6 Hz, 3H). 95 607.2(M + 1)/ δ 10.21-9.98 (m, 1H),8.30 (s, 1H), 7.76 606.19 for (s, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.46(br C29H30N6O7S d, J = 8.1 Hz, 1H), 7.11 (br d, J = 8.6 Hz, 1H), 6.96(s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 4.61 (s, 1H), 3.84 (s, 3H),3.78-3.73 (m, 5H), 3.70-3.58 (m, 4H), 3.57-3.52 (m, 2H), 2.60 (q, J =7.7 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H). 96 578.3(M + 1)/ δ 9.61 (s, 1H),7.83 (s, 1H), 7.71 (t, J = 577.16 for 8.0 Hz, 1H), 7.52-7.48 (m, 2H),7.45 (d, C28H27N5O7S J = 7.4 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H),6.81-6.76 (m, 2H), 4.62 (s, 1H), 4.03 (s, 3H), 3.86-3.81 (m, 2H), 3.79(s, 6H), 3.74- 3.69 (m, 2H), 3.64 (s, 4H). 97 584.1(M + 1)/ δ 9.58 (s,1H), 7.64 (d, J = 7.7 Hz, 2H), 583.12 for: 7.50 (t, J = 8.5 Hz, 1H),7.32 (s, 1H), 6.78 C26H25N5O7S2 (d, J = 8.6 Hz, 2H), 4.64 (s, 1H), 3.99(s, 3H), 3.91-3.83 (m, 2H), 3.78 (s, 6H), 3.70- 3.65 (m, 2H), 3.63-3.57(m, 2H), 3.56- 3.48 (m, 2H). 98 575.3(M + 1)/ δ 10.17-9.87 (m, 1H), 7.66(d, J = 2.3 Hz, 574.19 for 1H), 7.50-7.39 (m, 2H), 7.38-7.30 (m,C30H30N4O6S 1H), 7.28 (s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.12 (br d, J =8.5 Hz, 1H), 7.07-7.00 (m, 2H), 4.61 (s, 1H), 3.96 (s, 3H), 3.85 (t, J =5.0 Hz, 3H), 3.78 (s, 3H), 3.69-3.62 (m, 3H), 3.26-3.22 (m, 2H),2.65-2.57 (m, 2H), 1.16 (t, J = 7.6 Hz, 3H). 99 536.1(M + 1)/ δ 10.06(s, 1H), 7.78-7.59 (m, 1H), 7.51- 535.15 for 7.42 (m, 1H), 7.35 (s, 1H),7.17-7.07 (m, 1 C26H25N5O6S H), 6.95 (br d, J = 12.1 Hz, 1H), 6.77 (s,1H), 5.39 (d, J = 9.9 Hz, 2H), 4.77 (s, 1H), 4.65 (s, 1H), 4.57 (s, 1H),4.41 (br d, J = 19.5 Hz, 2H), 3.84 (d, J = 2.1 Hz, 3H), 3.74 (s, 3H),2.60 (q, J = 7.5 Hz, 2H), 1.18-1.09 (m, 3H). 100  591.3(M + 1)/ δ 9.56(br s, 1H), 7.50 (t, J = 8.4 Hz, 1H), 590.18 for 7.40 (s, 1H), 7.26 (t,J = 7.8 Hz, 1H), 7.06- C30H30N4O7S 6.93 (m, 3H), 6.86-6.74 (m, 3H),4.49- 4.45 (m, 1H), 4.38 (s, 1H), 4.02 (s, 3H), 3.94-3.87 (m, 1H), 3.79(s, 7H), 3.70 (s, 2H), 3.68-3.57 (m, 3H), 3.45-3.37 (m, 1H), 1.82 (quin,J = 5.7 Hz, 1H). 101  576.1(M + 1)/ δ 9.63 (brs, 1H), 7.66 (s, 1H), 7.62(d, J = 575.17 for 7.9 Hz, 1H), 7.50 (t, J = 8.5 Hz, 1H), 7.46-C30H29N3O7S 7.43 (m, 1H), 7.42-7.39 (m, 1H), 7.32 (d, J = 7.7 Hz, 1H),7.06 (s, 1H), 6.79 (s, 1H), 6.77 (s, 1H), 4.51-4.44 (m, 1H), 4.42-4.35(m, 2H), 4.02 (s, 3H), 3.79 (s, 6H), 3.28- 3.23 (m, 1H), 2.90 (tt, J =3.2, 12.1 Hz, 1H), 2.79 (dt, J = 2.7, 12.8 Hz, 1H), 1.96- 1.82 (m, 2H),1.77-1.55 (m, 2H). 102  584.1(M + 1)/ δ 9.66 (br s, 1H), 7.57-7.43 (m,2H), 7.23 583.12 for (d, J = 5.5 Hz, 2H), 6.78 (d, J = 8.6 Hz,C26H25N5O7S2 2H), 4.63 (s, 1H), 3.98 (s, 3H), 3.90-3.81 (m, 3H), 3.78(s, 6H), 3.71-3.62 (m, 3H), 3.25-3.18 (m, 2H). 103  522.2(M + 1)/ δ10.94-10.70 (m, 1H), 10.29 (br s, 1H), 521.15 for 8.29 (br d, J = 6.0Hz, 1H), 8.19-8.11 (m, C26H24FN5O4S 1H), 8.05 (br s, 1H), 7.83-7.74 (m,1H), 7.72-7.62 (m, 1H), 7.56-7.51 (m, 1H), 7.45-7.34 (m, 2H), 7.32-7.26(m, 1H), 6.91-6.82 (m, 1H), 4.64 (s, 1H), 3.88-3.79 (m, 3H), 3.70-3.59(m, 4H), 3.57-3.46 (m, 4H). 104  596.2(M + 1)/ δ 10.06 (br s, 1H), 7.65(d, J = 2.0 Hz, 595.16 for 1H), 7.51-7.44 (m, 1H), 7.40-7.34 (m,C28H29N5O6S2 1H), 7.12 (br dd, J = 5.2, 8.1 Hz, 2H), 7.01 (br d, J =10.0 Hz, 1H), 4.52 (s, 1H), 4.49 (s, 1H), 3.91 (s, 3H), 3.77-3.67 (m,8H), 3.61-3.55 (m, 2H), 3.55-3.46 (m, 2H), 2.64-2.55 (m, 1H), 1.97-1.81(m, 1H), 1.15 (t, J = 7.5 Hz, 3H). 105a 550.2(M + 1)/ δ 10.01 (br s,1H), 7.63 (s, 1H), 7.50-7.34 549.17 for (m, 2H), 7.11 (br d, J = 8.3 Hz,1H), 6.76 C27H27N5O6S (s, 1H), 6.69 (s, 1H), 5.35 (br s, 2H), 4.78- 4.45(m, 3H), 4.00-3.89 (m, 2H), 3.88- 3.78 (m, 4H), 3.74 (s, 3H), 2.85-2.55(m, 6H). 105b 550.2(M + 1)/ δ 10.28-9.89 (m, 1H), 7.63 (s, 1H), 7.52-549.17 for 7.36 (m, 2H), 7.11 (br d, J = 8.3 Hz, 1H), C27H27N5O6S 6.76(s, 1H), 6.69 (s, 1H), 5.35 (br s, 2H), 4.72 (s, 1H), 4.63 (s, 1H), 4.57(s, 1H), 4.50 (s, 1H), 3.99-3.90 (m, 1H), 3.86-3.79 (m, 3H), 3.74 (s,2H), 2.80-2.57 (m, 4H), 1.29-1.09 (m, 4H). 106  584.4(M + 1)/ δ 9.55 (s,1H), 7.91 (s, 1H), 7.56-7.45 (m, 583.12 for 1H), 7.22 (s, 1H), 6.95 (s,1H), 6.78 (d, J = C26H25N5O7S2 8.4 Hz, 2H), 4.64 (s, 1H), 3.97 (s, 3H),3.89-3.82 (m, 2H), 3.78 (s, 6H), 3.68-3.64 (m, 2H), 3.62-3.58 (m, 2H),3.54-3.50 (m, 1H), 3.46-3.45 (m, 1H), 107  526.3(M + 1)/ δ 8.15-8.13 (m,1H), 7.65 (d, J = 2.3 Hz, 525.12 for 1H), 7.48-7.39 (m, 1H), 7.38-7.23(m, C22H27N3O8S2 1H), 7.04-6.89 (m, 2H), 6.76-6.62 (m, 1H), 6.03 (s,1H), 5.99 (s, 1H), 5.92 (d, J = 10.0 Hz, 1H) 4.55 (s, 2H), 3.86 (s, 3H),3.71 (s, 3H), 3.50 (t, J = 5.6 Hz, 2H), 3.05 (q, J = 5.7 Hz, 2H),2.63-2.53 (m, 2H), 1.19-1.08 (m, 3H). 108  566.1(M + 1)/ δ 7.80 (s, 1H),7.53-7.42 (m, 2H), 7.34 (t, 565.13 for J = 5.9 Hz, 1H), 6.82 (s, 1H),6.78-6.74 C23H27N5O8S2 (m, 3H), 5.40 (s, 2H), 3.99 (d, J = 5.9 Hz, 2H),3.88 (s, 3H), 3.75 (s, 6H), 2.88 (q, J = 7.3 Hz, 2H), 2.07 (s, 1H), 1.09(t, J = 7.3 Hz, 3H). 109  512.1(M − 1)/ δ 9.98 (s, 1H), 7.64 (d, J = 2.3Hz, 1H), 513.16 for 7.46 (br d, J = 7.4 Hz, 1H), 7.11 (br d, J =C25H27N3O7S 6.9 Hz, 2H), 6.76 (s, 1H), 4.65-4.56 (m, 2H), 4.48 (s, 1H),4.43 (s, 1H), 4.21 (tt, J = 2.0, 4.3 Hz, 1H), 3.86 (s, 3H), 3.77- 3.68(m, 3H), 3.65-3.56 (m, 1H), 3.52- 3.34 (m, 2H), 2.60 (q, J = 7.5 Hz,2H), 2.17-1.90 (m, 2H), 1.18-1.11 (m, 3H). 110  514.2(M + 1)/ δ 9.97 (s,1H), 7.64 (d, J = 2.2 Hz, 1H), 513.16 for 7.45 (br s, 1H), 7.18-7.05 (m,2H), 6.76 (s, C25H27N3O7S 1H), 4.68-4.58 (m, 2H), 4.49-4.46 (m, 1H),4.42 (s, 1H), 4.24-4.18 (m, 1H), 3.86 (s, 3H), 3.75 (d, J = 1.3 Hz, 4H),3.32 (s, 14H), 2.61 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz, 4H). 111 538.3 (M + 1)/ δ 9.73 (s, 1H), 7.69-7.61 (m, 1H), 7.46 (s, 537.20 for1H), 7.39-7.33 (m, 1H), 7.31 (s, 1H), 7.23 C27H31N5O5S (d, J = 8.0 Hz,1H), 7.06 (d, J = 1.8 Hz, 1H), 7.03 (s, 1H), 4.61 (s, 1H), 4.02 (s, 3H),3.88-3.82 (m, 2H), 3.69-3.64 (m, 2H), 3.34 (br s, 3H), 3.28-3.24 (m,3H), 1.76 (br d, J = 8.5 Hz, 2H), 1.66-1.59 (m, 2H), 1.48 (br d, J =11.8 Hz, 1H), 1.24- 1.14 (m, 4H). 112  552.2 (M + 1)/ δ 10.09-9.91 (m,1H), 7.49-7.41 (m, 1H), 551.22 for 7.40-7.27 (m, 2H), 7.23 (br d, J =7.3 Hz, C28H33N5O5S 1H), 7.10-7.00 (m, 2H), 4.62 (s, 1H), 4.03 (s, 3H),3.85 (br d, J = 4.8 Hz, 2H), 3.82- 3.69 (m, 2H), 3.69-3.63 (m, 2H),3.27- 3.19 (m, 2H), 2.84 (s, 3H), 1.77-1.68 (m, 2H), 1.65-1.50 (m, 4H),1.44-1.31 (m, 2H), 1.29-1.19 (m, 2H), 1.11-1.09 (m, 1H). 113  578.25(M + H)/ δ 10.36-10.31 (m, 1H), 7.73-7.68 (m, 1H), 577.16 for 7.65-7.61(m, 1H), 7.53-7.44 (m, 2H), C28H27N5O7S 7.44-7.35 (m, 1H), 7.17-7.10 (m,1H), 6.83-6.74 (m, 2H), 4.63-(S, 1H), 4.08 (s, 3H), 3.89-3.85 (m, 2H),3.78 (br s, 6H), 3.70-3.65 (m, 2H), 3.27-3.21 (m, 2H) (2H merged withsolvent peak) 114  576.32 (M + H)/ 1H NMR (400 MHz, METHANOL-d4) 575.18for δ = 7.80 (d, J = 2.2 Hz, 1H), 7.72 (s, 1H), C29H29N5O6S 7.58 (d, J =8.2 Hz, 1H), 7.46 (dd, J = 2.1, 8.7 Hz, 1H), 7.42-7.38 (m, 1H), 7.35 (brs, 1H), 7.18-7.12 (m, 1H), 7.10-7.04 (m, 1H), 4.15 (s, 3H), 4.07-4.04(m, 1H), 4.04- 3.96 (m, 2H), 3.85 (s, 3H), 3.84-3.78 (m, 2H), 3.38-3.34(m, 4H), 2.72-2.62 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H) (exchangeable NHproton not observed) 115  593.20 (M + H)/ 1H NMR (400 MHz, METHANOL-d4)592.16 for δ = 7.50 (t, J = 8.5 Hz, 1H), 7.23 (s, 1H), C29H28N4O8S 6.99(s, 1H), 6.80-6.74 (m, 3H), 6.67-6.61 (m, 1H), 6.50 (t, J = 2.1 Hz, 1H),4.14 (s, 3H), 4.02-3.96 (m, 2H), 3.89 (s, 6H), 3.82- 3.76 (m, 2H),3.31-3.27 (m, 2H), 3.26- 3.22 (m, 2H) (2H exchangeable protons notobserved for NH and OH) 116  550.40 (M + H)/ δ 10.02 (br s, 1H), 7.80(s, 1H), 7.62 (d, 549.14 for J = 2.3 Hz, 1H), 7.45(s, 2H), 7.27 (t, J =C23H27N5O7S2 5.9 Hz, 1H), 7.10 (br d, J = 6.6 Hz, 1H), 6.85 (br s, 1H),6.79-6.68 (m, 1H), 5.39 (s, 2H), 4.01 (d, J = 5.9 Hz, 2H), 3.82 (s, 3H),3.74 (s, 3H), 2.81 (s, 3H), 2.64-2.54 (m, 2H), 1.14 (t, J = 7.6 Hz, 3H)117  537.47 (M + H)/ δ 10.47-10.38 (m, 1H), 7.50 (s, 1H), 7.39- 536.21for 7.29 (m, 2H), 7.24 (br d, J = 8.1 Hz, 1H), C28H32N4O5S 7.08-7.01 (m,2H), 4.61 (s, 1H), 4.04 (s, 3H), 3.90-3.82 (m, 2H), 3.72-3.64 (m, 2H),3.51-3.37 (m, 3H), 3.29-3.19 (m, 4H), 2.08-1.97 (m, 1H), 1.91-1.82 (m,2H), 1.72-1.64 (m, 2H), 1.62-1.58 (m, 1H), 1.33-0.99 (m, 4H). 118 584.00 (M + H)/ δ 9.73 (s, 1H), 7.67 (d, J = 1.0 Hz, 1H), 583.12 for7.51 (t, J = 8.4 Hz, 1H), 7.27 (d, J = 0.9 C26H25N5O7S2 Hz, 1H), 6.80(s, 1H), 6.78 (s, 1H), 6.56 (s, 1H), 4.61 (s, 1H), 4.01 (s, 3H), 3.88-3.83 (m, 2H), 3.78 (s, 6H), 3.70-3.63 (m, 2H), 3.43-3.37 (m, 2H),2.09-2.06 (m, 2H). 119  578.40 (M + H)/ δ 8.32 (d, J = 5.9 Hz, 1H), 7.87(s, 1H), 577.16 for 7.70-7.37 (m, 4H), 6.89 (dd, J = 2.3, 6.0C28H27N5O7S Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 4.63 (s, 1H), 4.01 (s,3H), 3.87-3.81 (m, 2H), 3.78 (s, 6H), 3.65-3.61 (m, 2H), 3.59-3.55 (m,2H), 3.54-3.50 (m, 2H). 120  561.40 (M + H)/ δ 8.17 (s, 1H), 7.86 (br s,1H), 7.44 (br t, 560.17 for J = 8.4 Hz, 2H), 7.37-7.28 (m, 1H), 6.99C29H28N4O6S (dd, J = 2.0, 8.4 Hz, 1H), 6.93 (s, 2H), 6.81 (d, J = 7.6Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 5.75 (s, 1H), 4.59 (s, 2H), 3.86-3.78 (m, 2H), 3.66-3.60 (m, 6H), 3.28- 3.24 (m, 2H), 3.23-3.17 (m, 2H),2.28- 2.25 (m, 3H). 121  418.40 (M + 1)/ δ 9.46 (broad s, 1H), 7.85 (d,J = 2.0 Hz, 417.53 for 1H), 7.47 (d, J = 1.6 Hz, 1H), 6.95 (s, 1H),C₂₀H₂₇N₅O₃S 6.46 (s, 1H), 6.28 (t, J = 2.0 Hz, 1H), 5.39 (s, 2H), 3.86(s, 3H), 3.82 (s, 3H), 3.23 (d, J = 6.0 Hz, 2H), 1.98-1.86 (m, 3H),1.66- 1.56 (m, 3H), 1.28-1.08 (m, 5H). 122  416.2 (M + 1)/ δ 10.26 (s,1H), 7.83 (d, J = 2.4 Hz, 1H), 415.44 for 7.70-7.63 (m, 2H), 7.46 (s,1H), 7.45-7.39 C₁₉H₁₈FN₅O₃S (m, 1H), 7.28 (t, J = 6.8 Hz, 1H), 6.91(broad s, 1H), 6.36 (broad s, 1H), 6.27 (t, J = 2.0 Hz, 1H), 5.36 (s,2H), 3.81 (s, 3H), 3.56 (s, 3H). 123  458.2 (M + 1)/ δ 8.89 (s, 1H),7.83 (d, J = 2.0 Hz, 1H), 457.51 for 7.47-7.41 (m, 2H), 6.88 (s, 1H),6.74 (d, C₂₁H₂₃N₅O₅S J = 8.4 Hz, 2H), 6.39 (s, 1H), 6.27 (s, 1H), 5.36(s, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H), 3.70 (s, 3H). 124 402.2 (M + 1)/ δ 12.71 (s, 1H), 10.23 (s, 1H), 7.83 (d, J = 401.42 for2.0 Hz, 1H), 7.72-7.63 (m, 2H), 7.47 (d, C18H16FN5O3S J = 1.6 Hz, 1H),7.43-7.39 (m, 1H), 7.31- 7.26 (s, 1H), 6.63 (s, 1H), 6.37 (s, 1H), 6.28(t, J = 2.0 Hz, 1H), 5.37 (s, 2H), 3.64 (s, 3H). 125  444.2 (M + 1)/ δ12.38 (s, 1H), 8.81 (s, 1H), 7.79 (s, 1H), 443.48 for 7.43 (s, 1H), 7.38(t, J = 8.4 Hz, 1H), 6.68 C₂₀H₂₁N₅O₅S (d, J = 8.4 Hz, 2H), 6.56 (s, 1H),6.37 (s, 1H), 6.24 (s, 1H), 5.33 (s, 2H), 3.74 (s, 3H), 3.71 (s, 3H),3.70 (s, 3H). 126  430.2 (M + 1)/ δ 10.41 (broad s, 1H), 8.72 (s, 1H),8.11 429.50 for (s, 1H), 7.03 (s, 1H), 6.82 (s, 1H), 5.52 (s,C₂₀H₂₃N₅O₄S 2H), 3.91 (s, 3H), 3.36-3.34 (m, 1H), 3.17 429.50 (d, J =3.2 Hz, 1H), 2.01-1.92 (m, 1H), 1.85 (d, J = 12.0 Hz, 2H), 1.66-1.53 (m,3H), 1.28-1.05 (m, 5H). 127  405.07 (M + 1)/ (400 MHz, MeOH-d4) δ 7.79(d, J = 2.0 404.16 for Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 6.62-C₁₈H₂₄N₆O₃S 6.57 (m, 1H), 6.39 (t, J = 2.0 Hz, 1H), 5.97 (broad s, 1H),5.36 (s, 2H), 4.00 (s, 3H), 3.14 (d, J = 4.0 Hz, 2H), 2.07-1.97 (m, 2H),1.73-1.63 (m, 3H), 1.37-1.07 (m, 6H). 128  434.55 (M + 1)/ δ 8.36 (broads, 2H), 7.92 (d, J = 2.0 Hz, 433.53 for 1H), 6.66 (s, 1H), 6.54 (s, 1H),6.37 (d, J = C₂₀H₂₇N₅O₄S 2.4 Hz, 1H), 5.37 (s, 2H), 4.01 (s, 2H), 3.79(s, 3H), 2.94 (d, J = 6.0 Hz, 2H), 1.86 (d, J = 12.4 Hz, 2H), 1.79-1.76(m, 1H), 1.61-1.53 (m, 3H), 1.24-1.05 (m, 3H), 0.94 (q, J = 11.2 Hz,2H). NH proton not observed. 129  490.10 (M + 1)/ δ 10.38 (s, 1H), 8.11(t, J = 5.6 Hz, 1H), 489.59 for 7.79 (d, J = 2.0 Hz, 1H), 6.92 (s, 1H),6.78 C23H31N5O5S (s, 1H), 6.15 (d, J = 2.4 Hz, 1H), 5.39 (s, 2H), 4.19(d, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.36 (d, J = 6.0 Hz, 2H), 2.09 (q, J= 7.6 Hz, 2H), 2.02-1.93 (m, 1H), 1.86 (d, J = 11.2 Hz, 2H), 1.68-1.54(m, 3H), 1.29- 1.02 (m, 5H), 0.99 (t, J = 7.6 Hz, 3H). 1H NMR indicatessingle isomer and the structure was further confirmed from its nOe study130  434.15 (M + 1)/ δ 10.41 (broad s, 1H), 7.95 (broad s, 2H), 433.53for 7.91 (s, 1H), 7.58 (s, 1H), 6.92 (s, 1H), C20H27N5O4S 6.83 (s, 1H),5.48 (s, 2H), 3.91 (merged s, 5H), 3.37 (merged d, J = 5.6 Hz, 2H),2.04-1.91 (m, 1H), 1.86 (d, J = 12.4 Hz, 2H), 1.61 (d, J = 12.4 Hz, 2H),1.59-1.51 (m, 1H), 1.29-1.04 (m, 5H).

Additional compounds, which can be prepared using methods disclosedherein and known to one of ordinary skill in the art and using readilyobtainable or commercially available starting materials, include thefollowing:

or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceuticallyacceptable salt thereof.

Additional compounds, which can be prepared using methods disclosedherein and known to one of ordinary skill in the art and using readilyobtainable or commercially available starting materials, include thefollowing:

or a stereoisomer, regioisomer or a mixture of stereoisomers, and/or apharmaceutically acceptable salt thereof.

Biological Example 1 Kat6a AlphaLISA Inhibition Screening Assay

The Kat6a inhibitory activity of test compounds was determined using anAlpha Screen-based detection method. The assay reactions were conductedin a volume of 10 μL in Alpha Plate, White 384 well plate (cat #6008280,Perkin Elmer). The enzymatic reactions were performed in assay buffer pH8.0 (50 mM Tris-HCl, 0.1 mM EDTA, 0.01% Tween-20, 1 mM Dithiothreitol,0.1% BSA (fatty acid free) and 330 nM TSA (Trichostatin A)). 10 μLreaction volume consisting of 25 nM of Recombinant KAT6A/MOZ (488-778)protein (Active motif, Catalog #81223), 400 nM Acetyl coenzyme A(Catalog #A2056, Sigma), 200 nM of Histone H₃ peptide [(amino acids1-21), biotin-labeled (BPS Biosciences, Catalog #52011,)] and a 10-pointdose response curve for test/tool compounds were prepared. Enzyme andcompounds solution were pre-incubated in assay plate for 60 or 10 min atroom temperature then substrate and Acetyl coenzyme A solution wereadded to the plate. After addition, the plate was sealed with adhesiveseals and incubated for 120 minutes at room temperature.

After 120 minutes of incubation, 5 μL (10 μg/mL) of AlphaLISAanti-acetyl-Lysine acceptor beads (Perkin Elmer, Catalog #AL143C) wereadded to the plate and it was incubated for 60 minutes at roomtemperature. Then 10 μL (10 μg/mL) of Alpha Streptavidin donor beads(Perkin Elmer, Catalog #6760002S) were added to the plate which wasfurther incubated for 60 minutes at room temperature. After incubation,the alpha signal was recorded by using Perkin Elmer Envision multi-modereader. Percent inhibition of enzyme activity was determined relative topositive control (1% DMSO) and IC₅₀ values were calculated usingGraphPad Prism software (four parameter-variable slope equation).

IC₅₀ data for compounds as tested according to Biological Example 1 areprovided in Table 2. NA means the compound was not active at theconcentration tested. A means the compound provided an IC₅₀ of ≤10 μM; Bmeans the compound provided an IC₅₀ of greater than 10 μM but less thanor equal to 20 μM; and C means the compound provided an IC₅₀ of greaterthan 20 μM but less than or equal to 50 μM. NT means not tested.

TABLE 2 Biochemical IC₅₀ of selected compounds are provided below.Synthetic Kat6A biochemical ZR-75-1: EC₅₀ Example No. assay: IC₅₀ (μM)(μM)  1 NT NT  2 A^(b) NT  3 A^(b) NT  4 A^(b) NT  5 A^(b) NT  6 A^(b) A 7 A^(b) NT  8 A^(a) NT  9 A^(a) NT 10 A^(a) NT 11 C^(a) NT 12 A^(a) NT13 A^(a) NT 14 C^(a) NT 15 A^(b) NT 16 A^(b) NT 17 A^(b) NT 18 A^(b) NT19 A^(b) NT 20 A^(b) NA > 10 21 A^(b) NA > 10 22 A^(b) NT 23 A^(b) NT 24A^(b) NT  25a A^(b) A  25b A^(b) NA > 10  26a A^(b) A  26b A^(b) NT  27aA^(b) NT  27b A^(b) A  28a A^(b) NT  28b B^(b) NT  29a A^(b) NT  29bA^(b) NT  30a A^(b) A  30b A^(b) A 31 A^(b) A 32 A^(b) A 33 A^(b) A 34A^(b) 35 A^(b) NT 36 A^(b) A 37 A^(b) A 38 A^(b) NT 39 C^(a) NT 40 NA >100^(a) NT 41 A^(b) NT 42 A^(b) NT 43 A^(b) A  27a A^(b) NT  27b A^(b) A44 A^(b) 45 A^(b) 46 A^(b) 47 A^(b) 48 A^(b) 49 A^(b) 50 A^(b) 51 A^(b)52 A^(b) 53 A^(b) 54 A^(b) 55 A^(b) 56 A^(b) 57 A^(b) 58 A^(b) 59 A^(b)60 A^(b) 61 A^(b) 62 A^(b) NT 63 NA^(b) > 10 NT 64 A^(b) 65 A^(b) 66A^(b) 67 NA^(b) > 10 68 A^(b) 69 A^(b) 70 A^(b) 71 A^(b) ^(a)10′pre-incubation ^(b)60′ pre-incubation

TABLE 3 Biochemical IC₅₀ data of selected compounds are provided below.Synthetic Kat6A Biochemical Example No. assay: IC50 (μM)  72 A^(b)  73A^(b)  74 A^(b)  75 NA^(b)  76 A^(b)  77 A^(b)  78 A^(b)  79 A^(b)  80A^(b)  81 A^(b)  82 A^(b)  83 A^(b)  84 A^(b)  85 A^(b)  86 NA^(b)  87A^(b)  88 A^(b)  89 A^(b)  90 A^(b)  91 A^(b)  92 A^(b)  93 A^(b)  94A^(b)  95 A^(b)  96 A^(b)  97 A^(b)  98 A^(b)  99 A^(b) 100 A^(b) 101A^(b) 102 A^(b) 103 A^(b) 104 A^(b)  105a A^(b)  105b A^(b) 106 A^(b)107 A^(b) 108 A^(b) 109 A^(b) 110 A^(b) 111 A^(b) 112 A^(b) 113 A^(b)114 NA^(b) 115 A^(b) 116 A^(b) 117 A^(b) 118 A^(b) 119 A^(b) 120 A^(b)121 B^(a) 122 C^(a) 123 B^(a) 124 C^(a) 125 A^(a) 126 A^(a) 127 A^(a)128 C^(a) 129 A^(a) 130 A^(a) ^(a)10′ pre-incubation ^(b)60′pre-incubation

Biological Example 2 Kat6a AlphaLISA Assay: Mechanism of Action Studyfor Reversibility/Irreversibility

Compounds may reversibly or irreversibly inhibit an enzyme in the MYSTfamily, including KAT6A and KAT6B. The following describes a two-stepmechanism of inhibition for covalent inhibitors.

In the above, E is the target enzyme, I is the inhibitor, E⋅I is thereversibly-bound protein-inhibitor complex, and E-I indicates thecovalent bond between the target enzyme and the inhibitor. K_(i) definesthe rate of the first reversible binding event. K₂ defines the maximumpotential rate of inactivation of the enzyme. K₊₂ defines the potentialrate of the reversibility of the binding event. Depending on the testconditions, an inhibitor may be a reversible inhibitor, an irreversibleinhibitor, or an inhibitor which progresses toward irreversibleinhibition given enough time.

The following protocol was used to determinereversibility/irreversibility of tested compounds.

Zeba™ Spin Desalting Columns, 7K MWCO, 0.5 mL (Catalog number: 89882,Thermo) were used for the assay. Columns were equilibrated by 5 washeswith assay buffer (50 mM Tris-HCl, 0.1 mM EDTA, 0.01% Tween-20, 1 mMdithiothreitol, 0.3% BSA (Fatty acid free) and 330 nM TSA (TrichostatinA).

100 nM concentration of Recombinant KAT6A/MOZ (488-778) protein (Activemotif, #81223) alone and with test compounds (20×concentration of IC₅₀)were incubated for 60 mins. at room temperature and added to spincolumns and further incubated for 10 mins. Separate tubes were preparedwith the same enzyme/test compound solutions, but were not passedthrough spin columns, and the tubes were incubated for 10 mins. The spincolumns were centrifuged at 1500 g, and flow-through were collected toassess activity. WM-1119 is a KAT6A inhibitor (J. Med. Chem. 2020, 63,4655-4684) and is used as a positive control.

Enzymatic reactions for samples passed through spin columns and sampleswhich were not passed through spin columns were performed in assaybuffer. 10 μL reaction volume consisting of 50 nM of RecombinantKAT6A/MOZ (488-778) protein (Active motif, #81223), 400 nM Acetylcoenzyme A (cat #A2056, Sigma), 200 nM of biotin-labelled histone H₃peptide (1-21)(Cat #52011, BPS Biosciences) and test compounds wereadded to a plate. After addition, the plate was sealed with adhesiveseals and incubated for 120 minutes at room temperature.

After 120 minutes of incubation, 5 μL (10 μg/mL) of AlphaLISAanti-ac-Lysine acceptor beads (cat #AL143C, Perkin Elmer) were added tothe plate, and the plate was incubated for 60 minutes at roomtemperature. 10 μL (10 μg/mL) of Alpha Streptavidin donor beads (cat#6760002S, Perkin Elmer) were added to the plate which was furtherincubated for 60 minutes at room temperature. After incubation, alphasignal was recorded by using Perkin Elmer Envision multi-mode reader. %Inhibition of enzyme activity was determined relative to positivecontrol (enzyme only) for both sample sets.

Data for selected compounds are shown below:

Kat6a AlphaLISA Assay: Spin Column % Inhibition Before Column AfterColumn Compounds N = 1 N = 2 N = 1 N = 2

98 98 14 40  Syn. Ex. 12 99 99 32 53 Syn. Ex. 7 95 96 2 17 Syn. Ex. 5100 98 102 95 Syn. Ex. 6 94 90 77 69  Syn. Ex. 13 99 98 100 91

The data above and in FIG. 1 demonstrate that WM-1119 is a reversibleinhibitor; Syn. Ex. 5, Syn. Ex. 6, and Syn. Ex. 13 are covalentinhibitors and are irreversibly bound to Kat6A; and Syn. Ex. 7 and Syn.Ex. 12 are reversible inhibitors under the experimental conditions usedto test the compounds.

Biological Example 3 In Vitro Cancer Cell Assay

ZR-75-1 and T47D are breast cancer cell lines containing high KAT6Aprotein expression. Proliferation of these cell lines are inhibited upontreatment with a KAT6A inhibitor. Cell line MCF7 is used as a negativecontrol. MCF7 cells have a low KAT6A protein expression and are notgrowth inhibited upon treatment with KAT6A inhibitors. WM-1119 is usedas a positive control.

1500 cells are seeded per well and incubated overnight at 37° C. and 5%CO₂. Cells are treated after 24 hours with a compound (stock solution,10 mM in DMSO) with 9-10 dilutions and a final DMSO concentration of0.5%. WM-1119 (10 μM top concentration, 9-10 point DRC, 3 fold dilutionin duplicate) is used as a positive control. Test compounds are testedlike WM-1119. Plates are incubated at 37° C. and 5% CO₂ for 10 days.Media is replenished after every alternate day. At day 10, Cell TiterGlow is added to the wells and luminescence is recorded after 10 minincubation. Data are normalized to 100% with DMSO control andsubtracting media blank. Cell viability is of the test compounds ismeasured.

The above procedure can be followed for determining activity inadditional cell lines, for example, ZR-75-1, T47D, CHAGOK1 and othercell lines that have high expression of KAT6A. The number of cells usedwill be optimized based on growth rate of the individual cell lines.

Biological Example 4 Liver Microsome Stability Assay

A microsomal mixture (microsomes and Kphos buffer) is prepared at aconcentration of 1.428 mg/mL in 2 mL tubes. To this microsomal mixture1.6 μL (1 mM) of test compound and positive control are spiked; fromthis mixture, 70 μL is transferred to 96 well plate and pre-incubated at37° C. for 5 min. After pre-incubation, the zero minute time pointreaction is stopped using 100 μL of ice-cold acetonitrile containinginternal standard and μL of NADPH (3.33 mM in Kphos buffer) is added.The 45-minute time point reaction is initiated by addition of 30 μL ofNADPH (3.33 mM in Kphos buffer) and incubated at 37° C. for 15 and 45min. Reactions without NADPH and buffer controls (minus NADPH) at 0, 15,and 45 minutes were also incubated to rule out non-NADPH metabolism orchemical instability in the incubation buffer. Incubation reactions werestopped with 100 μL of ice-cold acetonitrile containing internalstandard. The plates were centrifuged at 4000 RPM for 15 min and 100 μLaliquots were submitted for analysis by LC-MS/MS. (Verapamil in humanliver microsomes (HLM) and rat liver microsomes (RLM) was used aspositive controls. Imipramine in mouse liver microsomes (MLM) was usedas a positive control.) Samples were monitored for parent compounddisappearance in MRM mode (multiple reaction monitoring) using LC-MS/MS.The peak area ratios of analyte versus internal standard were used tocalculate the % remaining at the end of 45 minutes in the presence ofNADPH.

Biological Example 5 In Vivo Model

This model is used to evaluate the anti-cancer potential of testcompounds in 5-6-week old female Mus musculus (NOD.SCID) mice,NOD/MarkBomTac-Prkd^(scid), with a body weight of 15 to 20 g, bearing onZR-75-1 human breast adenocarcinoma xenograft. Animals are housed at atemperature of 19 to 25° C., a humidity of 30 to 70%, and watered adlibitum and fed ad libitum, except during fasting period. FemaleNOD.SCID (nulliparous non pregnant females) are allowed to acclimatizefor one to seven days prior to study initiation. During this period, themice are observed daily for clinical signs, mortality and morbidity, atleast once a day. Mice with any abnormalities or ill health or poorphysical condition are discarded. Female NOD.SCID mice bearing tumor arerandomized based on predetermined tumor size. Each group having meantumor volume ˜100-200 mm³ are selected in the final study andrandomized.

Dose formulations are prepared fresh every day prior to doseadministration. Test compounds are dissolved in a solvent such as DMSOat a suitable concentration and a dose volume of 10 mL/kg. Thetest/reference compound suspension formulation is administered orally tothe test groups.

ZR-75-1 (Human breast adenocarcinoma cell line) is maintained in RPMI1640 Medium and supplemented with 10% FBS and in an atmosphere air (with5% CO₂). The cells growing at log phase are washed two times with 1×PBSand harvested by trypsinization and then suspended in a required volumeof serum free medium. Cell viability is determined by trypan blueexclusion test. The aliquots of cell suspension containing 50×10⁶ MCF7cells/ml in serum free cell culture medium is prepared and diluted withequal volume of Matrigel to get 25×10⁶/mL cell suspension and placed onice to maintain the viability.

All female NOD.SCID mice are injected subcutaneously (SC) 17-β Estradiolpellets (0.72 mg-60 days release) 3-6 days before of ZR-75-1 cellsinoculation. The mice are then injected subcutaneously (SC) in the rightflank region with 0.2 mL of 5.0×10⁶ cell suspension (Serum free media:Matrigel; 1:1 ratio). After tumor development, tumor growth is measuredby digital vernier caliper. Further, tumor volume is calculated by theformula: Tumor volume (mm³)=(Length×Width²)/2. Animals whose tumorvolume reaches ˜100-200 mm³ are selected for the experiment andrandomized based on tumor volume (TV) into different groups G1-G6.

Clinical signs/mortality are observed daily. Body weight and tumor size(with a digital caliper) are measured at the time of randomization andthree times a week until the end of the experiment. Percentage change inthe body weight for each mouse are calculated as per the given formula:

${\%{Body}{Weight}{Change}} = {\frac{{{Body}{weight}{at}{day}x} - {{Initial}{Body}{weight}}}{{Initial}{Body}{weight}} \times 100}$

At the end of the study all the animals are humanely sacrificed afterlast dose and tumors carefully excised and weighed. Part of the tumor issnap frozen for western blot and another part is stored in formalin forIHC (optional) at −80° C. Mean Tumor growth inhibition (TGI) iscalculated from tumor volume data, according to the following formula.

$\frac{\begin{matrix}\left( {{{Mean}TV{of}{Vehicle}{Control}{on}{day}x} -} \right. \\\left. {{Mean}TV{of}a{Test}{Group}{on}{day}x} \right)\end{matrix}}{{Mean}TV{of}{Vehicle}{Control}{on}{day}x} \times 100$

All the individual animal data are summarized in terms of groups to getmean and standard error of mean (Mean±SEM). Data on each parameter isstatistically analyzed by using GraphPad prism and represented intabular and/or graphical form. All analysis and comparisons areevaluated at 5% level i.e. P≤0.05. The statistical analysis is performedusing GraphPad Prism statistical software and two-way ANOVA withBonferroni's post-hoc test or One-way ANOVA with Tukey's/Dunnett'spost-hoc test.

All publications, patents, and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication, patent, or patent application were specifically andindividually indicated to be incorporated by reference. While theclaimed subject matter has been described in terms of variousembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the claimed subject matter is limited solely by the scope ofthe following claims, including equivalents thereof.

What is claimed is:
 1. A compound of Formula (I):

wherein: R¹ is phenyl optionally substituted with 1, 2, or 3 R^(1b), or5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2,or 3 R^(1b); each R^(1b) is independently selected from hydrogen, halo,C₁-C₆alkyl, C₁-C₆alkoxy, hydroxyalkyloxy, —O-alkylene-NR^(1b1)R^(1b4),—O-alkylene-C(O)OR^(1b1), —O-alkylene-O-alkylene-NR^(1b1)R^(1b4),

 cyano, —(CH₂)₀₋₂C(O)—OR^(1b1), —(CH₂)₀₋₂C(O)NR^(1b1)R^(1b2),—(CH₂)₀₋₂NR^(1b1)C(O)R^(1b3), —(CH₂)₀₋₂OH, and C₃-C₈-cycloalkyloxy;R^(1b1) is hydrogen or C₁-C₆alkyl; R^(1b2) is hydrogen or C₁-C₆alkyl;R^(1b3) is hydrogen or C₁-C₆alkyl; and R^(1b4) is hydrogen,

R₂ is:

one X¹ is CR³ and the other X¹ are independently selected from CR^(2b);each R^(2b) is independently hydrogen, halo, —(CH₂)₀₋₂OH, C₁-C₃alkyl,cyclopropyl, cyano, —CHF₂, —CF₃, C₁-C₄alkoxy, —OCHF₂, —OCF₃, orC₃-C₈cycloalkyloxy; R^(2d) is hydrogen, halo, C₁-C₆alkyl,C₁-C₆cycloalkyl, C₁-C₆alkoxy, or C₃-C₈-cycloalkyloxy; R³ is—(CH₂)₀₋₂-L-Y; L is a bond or O; Y is a 5-membered monocyclic heteroarylsubstituted with R^(Y) and optionally substituted with R^(2e); Y is a6-membered monocyclic aryl or heteroaryl substituted with R^(Y) andoptionally substituted with 1 or 2 R^(2e); or Y is a 8- or 9-memberedbicyclic heterocyclic substituted with R^(Y) and optionally substitutedwith 1 or 2 R^(2e); each R^(2e) is independently hydrogen, —OH, halo,C₁-C₆alkyl, halo-C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆alkoxy,halo-C₁-C₆alkoxy, or C₃-C₈cycloalkyloxy; R^(Y) is—(CH₂)₀₋₃NR^(3b)C(O)R^(3a), —(CH₂)₀₋₂NR^(3b)S(O)₂R^(3a), —C(O)R^(3a),—S(O)₂R^(3a), —C(O)NR^(3b)R^(3a), or C₃-C₈heterocycloalkyl substitutedwith —C(O)R^(3a) R^(3a) is selected from C₁-C₆alkyl substituted with 1or 2 halo which are independently selected; C₁-C₆alkyl substituted withcyano; C₁-C₆alkyl substituted with fluoroalkoxy; C₁-C₆alkyl substitutedwith aryloxy or heteroaryloxy, each of which is optionally substitutedwith 1-3 substituents each independently selected from halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆alkoxy, cyano, C₃₋₈cycloalkyl or C₃₋₈heterocycloalkyl;C₂-C₆alkenyl; C₂-C₆alkenyl substituted with cyano; C₂-C₆alkenylsubstituted with halo; —CH═CH—CH₂—NR^(3c)R^(3d);—CH═CH—CH₂—O—C₁-C₆alkyl; C₃-C₈cycloalkenyl; —C(O)—C₃-C₈cycloalkyl;C₂-C₆alkynyl; —CH≡CH—CH₂—NR^(3c)R^(3d); CH≡CH—CH₂—OH;—CH≡CH—CH₂—O—C₁-C₆alkyl; spirocycloalkyl substituted with cyano;chloropyridyl; fluoropyridyl; chloropyrazinyl; fluoropyrazinyl;chloropyrimidinyl; fluoropyrimidinyl; pentafluorophenyl;tetraflurophenyl; trifluorophenyl, difluorophenyl; and monofluorophenyl;R^(3b) is selected from hydrogen, and C₁-C₆alkyl; or a pharmaceuticallyacceptable salt or salts thereof; and/or a stereoisomer or mixture ofstereoisomers thereof.
 2. The compound of claim 1, wherein R¹ is phenyloptionally substituted with 1, 2, or 3 R^(1b); or a pharmaceuticallyacceptable salt or salts thereof, and/or a stereoisomer or mixture ofstereoisomers thereof.
 3. The compound of claim 1, wherein R¹ is 5- or6-membered monocyclic heteroaryl optionally substituted with 1, 2, or 3R^(1b); or a pharmaceutically acceptable salt or salts thereof; and/or astereoisomer or mixture of stereoisomers thereof.
 4. The compound ofclaim 1, wherein each R^(1b) is independently selected from hydrogen,halo, —C(O)OH, —C(O)(OCH₃), C₁-C₆alkyl, and C₁-C₆alkoxy; or apharmaceutically acceptable salt or salts thereof, and/or a stereoisomeror mixture of stereoisomers thereof.
 5. The compound of claim 1, whereineach R^(1b) is independently selected from hydrogen, C₁-C₆alkyl, andC₁-C₆alkoxy; or a pharmaceutically acceptable salt or salts thereof,and/or a stereoisomer or mixture of stereoisomers thereof.
 6. Thecompound of claim 1, wherein one X¹ is CR³ and the other X¹ are CH; or apharmaceutically acceptable salt or salts thereof; and/or a stereoisomeror mixture of stereoisomers thereof.
 7. The compound of claim 1, whereinthe X¹ that is CR³ is in the meta position with respect to R^(2d). 8.The compound of claim 1, wherein R³ is —(CH₂)—Y; or a pharmaceuticallyacceptable salt or salts thereof; and/or a stereoisomer or mixture ofstereoisomers thereof.
 9. The compound of claim 1, wherein R³ is —L—Y;or a pharmaceutically acceptable salt or salts thereof; and/or astereoisomer or mixture of stereoisomers thereof.
 10. The compound ofclaim 1, wherein Y is a 5-membered monocyclic heteroaryl substitutedwith R^(Y); or a pharmaceutically acceptable salt or salts thereof,and/or a stereoisomer or mixture of stereoisomers thereof.
 11. Thecompound of claim 1, wherein Y is a pyrazolyl substituted with R^(Y); ora pharmaceutically acceptable salt or salts thereof; and/or astereoisomer or mixture of stereoisomers thereof.
 12. The compound ofclaim 1, wherein each R^(3b) is hydrogen; or a pharmaceuticallyacceptable salt or salts thereof, and/or a stereoisomer or mixture ofstereoisomers thereof.
 13. The compound of claim 1, wherein R^(Y) is—(CH₂)₀₋₃NHC(O)R^(3a); or a pharmaceutically acceptable salt or saltsthereof, and/or a stereoisomer or mixture of stereoisomers thereof. 14.The compound of claim 1, wherein R^(3a) is C₂-C₄alkenyl substituted withhalo; or C₂-C₆alkynyl; or a pharmaceutically acceptable salt or saltsthereof, and/or a stereoisomer or mixture of stereoisomers thereof. 15.The compound of claim 1, wherein R^(Y) is

or a pharmaceutically acceptable salt or salts thereof; and/or astereoisomer or mixture of stereoisomers thereof.
 16. The compound ofclaim 1, selected from

or a stereoisomer, a mixture of stereoisomers, and/or a pharmaceuticallyacceptable salt thereof.
 17. A compound of Formula (I):

wherein: R¹ is phenyl optionally substituted with 1, 2, or 3 R^(1b); or5- or 6-membered monocyclic heteroaryl optionally substituted with 1, 2,or 3 R^(1b); each R^(1b) is independently selected from H, halo,C₁-C₆alkoxy, cyano and C₃-C₈-cycloalkyloxy; R² is:

wherein, one X¹ is C(CH₂R^(2c)) or C(OR^(2c)), and the other two X¹ areindependently selected from N and CR^(2e); wherein C(CH₂R^(2c)) orC(OR^(2c)) is in the meta-position with respect to R^(2d); R^(2c) is a5-membered monocyclic heteroaryl substituted with R^(2c2) and optionallysubstituted with R^(2c3); R^(2c) is a 8- or 9-membered bicyclicheterocyclic substituted with R^(2c2) and optionally substituted withR^(2c3); or R^(2c) is a 6-membered monocyclic heteroaryl substitutedwith R^(2c2) and optionally substituted with 1 or 2 R^(2c3); R^(2c2) isC₁-C₆alkylcarbonyl, —CN, —CH₂NH₂, C₁-C₆alkoxy, —NH(C₁-C₆alkyl),—N(C₁-C₆alkyl)₂, —CH₂NHC(O)R^(2f), —(CH₂)₀₋₁NHC(O)OR^(2f), 5- or6-membered monocyclic heteroaryl, or 9- or 10-membered bicyclicheteroaryl; wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl, orC₃-C₆cycloalkylC₁-C₃alkyl; R^(2c3) is independently H, halo, C₁-C₆alkyl,C₁-C₆alkoxy, or C₃-C₈cycloalkyloxy; R^(2d) is halo, C₁-C₆alkyl,C₁-C₆alkoxy, or C₃-C₈-cycloalkyloxy; and each R^(2e) is independentlyhydrogen, halo, C₁-C₃alkyl, cyclopropyl, —CHF₂, —CF₃, C₁-C₄alkoxy,—OCHF₂, or —OCF₃; or a pharmaceutically acceptable salt or saltsthereof; and/or a stereoisomer or mixture of stereoisomers thereof. 18.The compound of claim 17, wherein R¹ is phenyl optionally substitutedwith 1, 2, or 3 R^(1b); or a pharmaceutically acceptable salt or saltsthereof, and/or a stereoisomer or mixture of stereoisomers thereof. 19.The compound of claim 17, wherein R¹ is 5- or 6-membered monocyclicheteroaryl optionally substituted with 1, 2, or 3 R^(1b); or apharmaceutically acceptable salt or salts thereof; and/or a stereoisomeror mixture of stereoisomers thereof.
 20. The compound of claim 17,wherein each R^(1b) is independently selected from H, halo, andC₁-C₆alkoxy; or a pharmaceutically acceptable salt or salts thereof,and/or a stereoisomer or mixture of stereoisomers thereof.
 21. Thecompound of claim 17, wherein R^(2d) is C₁-C₃alkoxy; or apharmaceutically acceptable salt or salts thereof, and/or a stereoisomeror mixture of stereoisomers thereof.
 22. The compound of claim 17,wherein R^(2e) is hydrogen; or a pharmaceutically acceptable salt orsalts thereof; and/or a stereoisomer or mixture of stereoisomersthereof.
 23. The compound of claim 17, wherein one X¹ is C(CH₂R^(2c)) orC(OR^(2c)), and the other two X¹ are each CH; or a pharmaceuticallyacceptable salt or salts thereof, and/or a stereoisomer or mixture ofstereoisomers thereof.
 24. The compound of claim 17, wherein R^(2c) is a5-membered monocyclic heteroaryl substituted with R^(2c2) and optionallysubstituted with R^(2c3); or a pharmaceutically acceptable salt or saltsthereof; and/or a stereoisomer or mixture of stereoisomers thereof. 25.The compound of claim 17, wherein R^(2c) is pyrazolyl substituted withR^(2c2) and optionally substituted with R^(2c3); or a pharmaceuticallyacceptable salt or salts thereof, and/or a stereoisomer or mixture ofstereoisomers thereof.
 26. The compound of claim 17, wherein R^(2c) is a6-membered monocyclic heteroaryl substituted with R^(2c2) and optionallysubstituted with 1 or 2 R^(2c3); or a pharmaceutically acceptable saltor salts thereof, and/or a stereoisomer or mixture of stereoisomersthereof.
 27. The compound of claim 17, wherein R^(2c2) is—(CH₂)₀₋₁NHC(O)OR^(2f); wherein R^(2f) is C₁-C₆alkyl, C₃-C₆cycloalkyl,or C₃-C₆cycloalkylC₁-C₃alkyl; or a pharmaceutically acceptable salt orsalts thereof; and/or a stereoisomer or mixture of stereoisomersthereof.
 28. The compound of claim 17, wherein each R^(2c3) is hydrogen;or a pharmaceutically acceptable salt or salts thereof, and/or astereoisomer or mixture of stereoisomers thereof.
 29. A pharmaceuticalcomposition comprising a compound of claim 1 or a stereoisomer, amixture of stereoisomers, and/or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.